17 Gardner - ch17 p595 682 PDF

17
C H A P T E R
Pancreatic Hormones and

Diabetes Mellitus
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Umesh Masharani, MB, BS, MRCP (UK) and

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Michael S. German, MD
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ABCC8 ATP-binding cassette transporter sub- ER Endoplasmic reticulum

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family C member 8 FDA Food and Drug Administration

ACE Angiotensin-converting enzyme FFA Free fatty acid
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ADA American Diabetes Association FHR Fetal heart rate

ADH Antidiuretic hormone (vasopressin) Foxo1 Forkhead box, subfamily O, member 1
AGE Advanced glycation end product FOXP3 Forkhead box, subfamily P, member 3
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AGPAT 1-acylglycerol-3-phosphate-O- GABA Gamma-aminobutyric acid

acyltransferase 2
GAD Glutamic acid decarboxylase
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AKT/PKB AKR mouse tumor 8 kinase/protein

kinase B GCK Glucokinase
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AIRE Autoimmune regulator GH Growth hormone

ALT Alanine aminotransferase GHb Glycohemoglobin
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AMPK Adenosine monophosphate-activated GHSR Growth hormone-secretagogue receptor

protein kinase GI Glycemic index
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APS1 Autoimmune polyendocrinopathy GIP Gastric inhibitory polypeptide

syndrome type 1 GLIS3 Glioma-associated oncogene homolog—
ATF6 Activating transcription factor 6 similar 3
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BMI Body mass index GLP-1 Glucagon-like peptide-1

cAMP Cyclic adenosine monophosphate GLP-2 Glucagon-like peptide-2
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CCK Cholecystokinin GLUT Glucose transporter

CEL Carboxyl-ester lipase GPCR G protein–coupled receptor
cGMP GRPP Glicentin-related polypeptide
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Cyclic 3′,5′-guanosine monophosphate

CIDEC Cell death-inducing DFFA-like effector C GWAS Genome-wide association study
CSII Continuous subcutaneous insulin infusion HDL High-density lipoprotein
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CST Contraction stress test HLA Human leukocyte antigen

CTLA4 Cytotoxic T-lymphocyte-associated HNF Hepatocyte nuclear factor
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protein 4
hPL Human placental lactogen
DCCT Diabetes Control and Complications Trial
IA2 Insulinoma antigen 2
DIDMOAD Diabetes insipidus, diabetes mellitus, optic
atrophy, deafness (Wolfram syndrome) IAA Insulin autoantibody
DPP Diabetes Prevention Program IAPP Islet amyloid polypeptide
DPP-4 Dipeptidyl peptidase 4 ICA Islet cell antibody
DPT-1 Diabetes Prevention Trial-1 IFG Impaired fasting glucose
EIF2AK3 Eukaryotic translation initiation factor IGF-1 Insulin-like growth factor 1
2-α kinase 3 IGT Impaired glucose tolerance
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596 CHAPTER 17 Pancreatic Hormones and Diabetes Mellitus
IL-6 Interleukin-6 PERK Protein kinase R-like endoplasmic

INS Insulin reticulum kinase
IP3 Inositol 1,4,5-triphosphate PGC1` PPAR gamma coactivator-1α
IPEX Immunodysregulation PNDM Permanent neonatal diabetes mellitus
polyendocrinopathy enteropathy, POEMS Polyneuropathy, organomegaly,
X-linked endocrinopathy, monoclonal
IPF-1 Insulin promoter factor-1 gammopathy, and skin changes
IRE1 Inositol-requiring enzyme 1 PP Pancreatic polypeptide
IRS Insulin receptor substrate PPAR Peroxisome proliferator-activated receptor
PTF1A
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ISL1 Islet transcription factor 1 Pancreatic transcription factor 1α

IUGR Intrauterine growth restriction PTP1b Protein tyrosine phosphatase 1b
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KPD Ketosis-prone diabetes RFX6 Regulatory factor X-6

KCNJ11 Potassium inwardly-rectifying channel, RXR 9-cis-retinoic acid receptor
subfamily J, member 11 SCL19A2 Solute carrier family 19 (thiamine
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Kir6.2 Potassium channel, inwardly-rectifying 6.2 transporter), member 2

LADA Latent autoimmune diabetes of SOCS Suppressor of cytokine signaling
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adulthood SREBP1c Sterol regulatory element-binding

LKB1 Liver kinase B1 protein 1c
SSTR Somatostatin receptor
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LDL Low-density lipoprotein

MAPK Mitogen-activated protein kinase SUR1 Sulfonylurea receptor 1
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MODY Maturity-onset diabetes of the young TCF7L2 Transcription factor 7-like 2

MHC Major histocompatibility complex TGF-a Transforming growth factor-β
mTOR Mammalian target of rapamycin TNDM Transient neonatal diabetes mellitus
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NeuroD1 Neural differentiation factor 1 TNF-` Tumor necrosis factor-α

Neurog3 Neural genesis factor 3 Ucn3 Urocortin3
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NIH National Institutes of Health UGDP University Group Diabetes Program

NPH Neutral protamine hagedorn UKPDS United Kingdom Prospective Diabetes
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Study
NST Nonstress test
VEGF Vascular endothelial growth factor
PAI-1 Plasminogen activator inhibitor-1
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VLDL Very low density lipoprotein

PAX4 Paired homeobox 4
VNTR Variable number of tandem repeats
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PCSK Proprotein convertase, subtilisin/kexin

PD-1 Programmed death 1 WFS1 Wolfram syndrome protein 1
PD-L1 Programmed death ligand 1 ZAC Zinc finger protein-inducing apoptosis
PDE5 Phosphodiesterase type 5 and cell cycle arrest
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PDX1 Pancreatic duodenal homeobox-1 ZnT8 Zinc transporter 8

ZFP57
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Zinc finger protein 57
THE ENDOCRINE PANCREAS ANATOMY AND HISTOLOGY

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The pancreas comprises two functionally distinct organs: the exo- The endocrine pancreas consists of approximately 1 million small
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crine pancreas, the major digestive gland of the body; and the endocrine glands—the islets of Langerhans—scattered through-
endocrine pancreas, the source of insulin, glucagon, somatosta- out the glandular substance of the exocrine pancreas. The exocrine
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tin, pancreatic polypeptide (PP), and ghrelin. Whereas the major pancreas consists of the enzyme-producing cells organized into
role of the products of the exocrine pancreas (the digestive acini, and the duct system that delivers those enzymes to the
enzymes) is the processing of ingested foodstuffs so that they lumen of the duodenum. The islet volume comprises 1% to 1.5%
become available for absorption, the hormones of the endocrine of the total mass of the pancreas and weighs about 1 to 2 g in adult
pancreas modulate every other aspect of cellular nutrition from humans. At least five cell types—α, β, δ, ε, and PP—have been
rate of adsorption of foodstuffs to cellular storage or metabolism identified in the islets (Table 17–1). Each of these islet cell types
of nutrients. Dysfunction of the endocrine pancreas or abnormal produces a distinguishing peptide hormone: glucagon, insulin,
responses to its hormones by target tissues cause serious distur- somatostatin, ghrelin, and PP, respectively. Within individual
bances in nutrient homeostasis, including the important clinical islets, the different cell types are scattered throughout. A typical
syndromes grouped under the name diabetes mellitus. human islet is depicted in Figure 17–1.

CHAPTER 17 Pancreatic Hormones and Diabetes Mellitus 597
TABLE 17–1 Cell types in adult human pancreatic of the surrounding exocrine pancreatic tissue. Each islet is sur-
islets of Langerhans. rounded by a lattice of astroglial cells and innervated by sympa-
thetic, parasympathetic, and sensory neurons.
Approximate
Percentage of
Cell Types Islet Volume Secretory Products
HORMONES OF THE ENDOCRINE
a Cell 25 Glucagon, proglucagon PANCREAS
β Cell 55 Insulin, C peptide, proinsulin, IAPP,
Ucn3, γ-aminobutyric acid (GABA)
1. INSULIN
δ Cell 10 Somatostatin-14
Biosynthesis
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ε Cell 3 Ghrelin
PP cell 5 Pancreatic polypeptide The human insulin gene resides on the short arm of chromosome
11. A unique set of transcription factors found in the β cell
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nucleus activates the transcription of the preproinsulin mRNA

These cell types are not distributed uniformly throughout the from the insulin gene (Figure 17–2). A precursor molecule, prep-
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pancreas. The PP cells reside primarily in islets in the posterior roinsulin, a peptide of MW 11,500, is translated from the prep-
portion (posterior lobe) of the head, a discrete lobe of the pancreas roinsulin messenger RNA in the rough endoplasmic reticulum of
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separated from the anterior portion by a fascial partition. This pancreatic β cells (see Figure 17–2). Microsomal enzymes cleave
lobe originates in the primordial ventral bud as opposed to the preproinsulin to proinsulin (MW ~9000) almost immediately
dorsal bud. The posterior lobe receives its blood supply from the after synthesis. Proinsulin is transported to the Golgi apparatus,
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superior mesenteric artery; the remainder of the pancreas derives where packaging into clathrin-coated secretory granules takes
most of its blood flow from the celiac artery. The islets themselves place. Maturation of the secretory granule is associated with loss
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are richly vascularized, receiving five to ten times the blood flow of the clathrin coating and conversion of proinsulin into insulin
and a smaller connecting peptide, or C peptide, by proteolytic
cleavage at two sites along the peptide chain. Mature secretory
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granules contain insulin and C peptide in equimolar amounts and

only small quantities of proinsulin, a small portion of which con-
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sists of partially cleaved intermediates.

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Biochemistry
Proinsulin (Figure 17–3) consists of a single chain of 86 amino
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acids, which includes the A and B chains of the insulin molecule

plus a connecting segment of 35 amino acids. Two proteins—the
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prohormone-converting enzymes type 1 and 2 (PCSK1 and

PCSK2)—are packaged with proinsulin in the immature secretory
granules. These enzymes recognize and cut at pairs of basic amino
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acids, thereby removing the intervening sequence. After the two

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pairs of basic amino acids are removed by carboxypeptidase E, the

result is a 51 amino acid insulin molecule and a 31 amino acid
residue, the C peptide, as shown in Figure 17–3.
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A small amount of proinsulin produced by the pancreas

escapes cleavage and is secreted intact into the bloodstream, along
with insulin and C peptide. Most anti-insulin sera used in the
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standard immunoassay for insulin cross-react with proinsulin;

about 3% to 5% of immunoreactive insulin extracted from
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human pancreas is actually proinsulin. Because proinsulin is not

removed by the liver, it has a half-life three to four times that of
insulin. Its long half-life allows proinsulin to accumulate in the
blood, where it accounts for 12% to 20% of the circulating immu-
FIGURE 17–1 Human islet of Langerhans. Staining for insulin
noreactive insulin in the basal state in humans. Human proinsulin
(red), glucagon (green), and somatostatin (blue) was performed by
immunofluorescence and imaged by confocal microscopy. (Repro-
has about 7% to 8% of the biologic activity of insulin. The kidney
duced with permission from Cabrera O, Berman DM, Kenyon NS, et al. is the principal site of proinsulin degradation.
The unique cytoarchitecture of human pancreatic islets has Of the two major proinsulin split products present in plasma,
implications for islet cell function. Proc Natl Acad Sci U S A. 2006 the one split at arginine 32-33 far exceeds in amount the barely
Feb 14;103(7):2334-2339.) detectable 65-66 split product. In control subjects, concentrations

Secretory granules (condensation and

storage of insulin)
Golgi (packaging of proinsulin into coated

secretory granules, conversion of proinsulin
to insulin)
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Ca2+ Small transfer vesicles (transport of proinsulin

to Golgi)
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Glucose
Nucleus (production of mRNA for preproinsulin

production)
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Mitochondrion
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Granular endoplasmic reticulum (synthesis of

preproinsulin; this is cleaved by microsomal
enzymes)
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FIGURE 17–2 Structural components of the pancreatic β cell involved in glucose-induced biosynthesis and release of insulin. (Modified
with permission from Junqueira LC, Carneiro J, Long JA. Basic Histology, 5th ed. New York: McGraw-Hill Education; 1986.)
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LEU SER GLY ALA GLY PRO

PRO GLN GLY
LEU GLY
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ALA GLY
LEU Connecting peptide LEU
GLU
GLU 10
GLY VAL
SER GLN
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C chain
LEU GLY
Dipeptide
linkage 31 GLN VAL
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LYS
GLN
ARG
LEU
1 GLY
C chain
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ASP
ILE
−COOH GLU
− VAL ASN
NH2 21
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ALA
GLU A chain CYS
PHE S GLU 1
1 GLN S TYR
VAL CYS ASN ARG
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CYS A chain GLU

ASN THR LEU ARG
B chain SER
ILE CYS SER LEU TYR GLN S
GLN S THR
HIS 10 B chain LYS 30
LEU S PRO
CYS Insulin S THR Dipep-
TYR tide
GLY PHE
SER
HIS B chain PHE linkage
LEU GLY
VAL ARG
10 GLU ALA GLY GLU
LEU TYR LEU VAL CYS
20
FIGURE 17–3 Structure of human proinsulin C peptides and insulin molecules connected at two sites by dipeptide links.

of proinsulin and 32-33 split proinsulin after an overnight fast 30 to 45 minutes, and then rapidly declines to baseline values by
averaged 2.3 and 2.2 pmol/L, respectively, with corresponding 90 to 120 minutes postprandially.
postprandial rises to 10 and 20 pmol/L. Basal insulin secretion occurs in the absence of exogenous stimuli,
C peptide, the 31 amino acid peptide (MW 3000) released in the fasting state. Plasma glucose levels below 80 to 100 mg/dL
during cleavage of insulin from proinsulin, has no known biologic (4.4-5.6 mmol/L) do not stimulate insulin release, and most other
activity. β Cells release C peptide in equimolar amounts with physiologic regulators of insulin secretion only function in the pres-
insulin. It is not removed by the liver but is degraded or excreted ence of stimulatory levels of glucose. Stimulated insulin secretion
chiefly by the kidney. It has a half-life three to four times that of occurs in response to exogenous stimuli. In vivo, ingested meals
insulin. In the basal state after an overnight fast, the average con- provide the major stimuli for insulin secretion. Glucose is the most
centration of C peptide may remain as high as 1000 pmol/L. potent stimulant of insulin release. The perfused pancreas releases
Insulin is a protein consisting of 51 amino acids contained insulin in two phases in response to glucose stimulation (Figure
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within two peptide chains: an A chain, with 21 amino acids; and 17–4). When the glucose concentration increases suddenly, an ini-
a B chain, with 30 amino acids. The chains are connected by two tial short-lived burst of insulin release occurs (the first phase); if the
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disulfide bridges as shown in Figure 17–3. In addition, an intra- glucose elevation persists, the insulin release gradually falls off and
chain disulfide bridge links positions 6 and 11 in the A chain. then begins to rise again to a steady level (the second phase). How-
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Human insulin has a molecular weight of 5808. ever, sustained levels of high glucose stimulation (~4 hours in vitro
Endogenous insulin has a circulatory half-life of 3 to 5 minutes. or >24 hours in vivo) result in a reversible desensitization of the β
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It is degraded chiefly by insulinases in liver, kidney, and placenta. cell response to glucose but not to other stimuli.
A single pass through the liver removes approximately 50% of the The β cell senses glucose through its metabolism (Figure
plasma insulin. 17–5). Indeed, agents such as 2-deoxyglucose that inhibit the
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metabolism of glucose block the release of insulin. Glucose enters

the pancreatic β cell by passive diffusion, facilitated by membrane
Secretion
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proteins termed glucose transporters (GLUTs) (discussed later).

The human pancreas secretes about 30 units of insulin per day Because the transporters function in both directions, and the β cell
into the portal circulation of normal adults in distinct pulses with has an excess of GLUTs, the glucose concentration inside the β cell
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a period of approximately 5 minutes. The basal concentration of is in equilibrium with the extracellular glucose concentration. The
insulin in the peripheral blood of fasting humans averages 10 μU/mL low-affinity enzyme glucokinase catalizes the subsequent, and
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(0.4 ng/mL, or 61 pmol/L). In normal control subjects, insulin rate-limiting, step in glucose metabolism by the pancreatic β cell,
seldom rises above 100 μU/mL (610 pmol/L) after standard the phosphorylation of glucose to glucose-6-phosphate. Glucose
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meals. After ingestion of food, peripheral insulin concentration catabolism in the β cell causes a rise in the intracellular ATP-ADP
increases within 8 to 10 minutes, reaches peak concentrations by ratio. Acting through the sulfonylurea receptor (SUR1), the
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80 Glucose
300
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Period of glucose infusion

60
up
Insulin (ng/mL)
Glucose (mg/dL)
Insulin
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40
150
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20
0 0
10 20 30 40 50 60
Minutes
FIGURE 17–4 Multiphasic response of the in vitro perfused rat pancreas during constant stimulation with glucose. (Modified with
permission from Grodsky GM, Curry D, Landahl H, et al. Further studies on the dynamic aspects of insulin release in vitro with evidence for a
two-compartmental storage system. Acta Diabetol Lat. 1969 Sep;6 Suppl 1:554-578.)

Glucose Catecholamines GLP-1

Glucose α2A GLP-1
transporter receptor receptor
Gαi Gαs
Glucose –
Insulin
cAMP Secretion
synthesis
Acetylcholine
Glucokinase
M3
Gαq
R
receptor
Ca2+
DAG and Voltage-gated

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Fructose 1,6-P2
other signals? calcium channel
Ca2+
ATP/ADP↑
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Phosphoenolpyruvate
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Kir6.2
K+
–
ATP-sensitive
SUR1
C
TCA potassium
cycle Fatty acids channel
amino acids
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Sulfonylureas
Pyruvate Acetyl CoA Mitochondria
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FIGURE 17–5 A simplified outline of glucose-sensing and regulated insulin secretion from the β cell. The blue arrows indicate stimulation,
and the red lines indicate inhibition. Glucose enters the β cell through facultative glucose transporters, is phosphorylated to glucose-6-phosphate by
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glucokinse, and enters glycolysis. This results in the production of pyruvate, which enters the mitochondria, is converted to acetyl-CoA, and
feeds the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to produce ATP. When ATP levels rise or sulfonylureas bind to the regula-
tory subunit (SUR1/ABCC8) of the ATP-sensitive K+ channels, the channel subunit (Kir6.2/KCNJ11) closes. This block of the K+ current depolarizes
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the cell, allowing the voltage-gated calcium channels to open. The entry of calcium drives the fusion of insulin granules with the cell surface
membrane and exocytosis of insulin. Glucose metabolism and extracellular signals modulate this pathway through release of Ca2+ from intracel-
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lular stores and changes in diacylglycerol (DAG), cAMP, and other intracellular signaling pathways.
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nucleotide-sensing subunit of the ATP-sensitive potassium chan- cytoplasmic Ca2+ concentration. The exact mechanisms of these
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nels on the surface of the β cell, the rise in ATP-ADP ratio closes amplifying signals remains unknown but involve multiple path-
the potassium channels and depolarizes the cell, thereby activating ways and include increases in the intracellular signaling molecules
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the voltage-sensitive calcium channels and allowing the entry of diacylglycerol and cAMP. Secretagogues such as the gut hormones
calcium ions into the cell. glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypep-
Insulin release requires calcium ion signaling. In addition to tide (also known as glucose-dependent insulinotropic peptide,
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the voltage-dependent entry of extracellular Ca2+ into the β cell as GIP) that act via GPCRs of the Gαs class also stimulate insulin
described earlier, glucose also retards Ca2+ efflux from the β cell secretion through elevations in cAMP.
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and releases Ca2+ from intracellular compartments (predomi- Other factors involved in the regulation of insulin secretion are
nantly the endoplasmic reticulum) into the cytosol. Some nonglu- summarized in Table 17–2. These factors can be divided into
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cose stimuli of insulin release also function through increases in three categories: direct stimulants, which directly raise cytoplas-
cytoplasmic Ca2+. The sulfonylurea and meglitinide (such as repa- mic calcium ion concentrations and thus can act in the absence of
glinide) medications act by closing the ATP-sensitive potassium stimulatory glucose concentrations; amplifiers, which potentiate
channels. Secretagogues such as acetylcholine that act through G the response of the β cell to glucose; and inhibitors. Many of the
protein–coupled receptors (GPCRs) of the Gαq class stimulate the amplifiers are incretins: gastrointestinal hormones that are released
release of intracellular Ca2+ stored in the endoplasmic reticulum in response to the ingestion of meals and stimulate insulin secre-
by activating phospholipase C and releasing the intracellular sig- tion. The action of the incretins explains the observation that
naling molecule inositol 1,4,5-triphosphate (IP3). orally ingested glucose provokes a greater insulin secretory
Glucose metabolism in the β cell also generates additional response than does the same amount of intravenously adminis-
signals that amplify the secretory response to elevations in tered glucose.

TABLE 17–2 Regulation of insulin release. cells, binding of insulin to these receptors is associated with the
biologic response of these tissues to the hormone. These receptors
Stimulants of Insulin Glucose bind insulin rapidly, with high specificity and with an affinity high
Release Amino acids: Leucine
Neural: Vagal stimulation, acetylcholine enough to bind picomolar amounts.
Drugs: Sulfonylureas, meglitinides Insulin receptors, members of the growth factor receptor fam-
Amplifiers of Glucose- Enteric hormones: ily (see Chapter 1), are membrane glycoproteins composed of two
Induced Insulin Glucagon-like peptide 1 (7-37) (GLP1) protein subunits encoded by a single gene. The larger alpha sub-
Release Gastric inhibitory peptide (GIP) unit (MW 135,000) resides entirely extracellularly, where it binds
Cholecystokinin, gastrin
the insulin molecule. The alpha subunit is tethered by disulfide
Secretin
Neural: β-adrenergic effect of linkage to the smaller beta subunit (MW 95,000). The beta sub-
unit crosses the membrane, and its cytoplasmic domain contains
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catecholamines
Amino acids: arginine a tyrosine kinase activity that initiates specific intracellular signal-
Drugs: GLP1 agonists
ing pathways.
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Inhibitors of Insulin Neural: α-adrenergic effect of

Release catecholamines Downstream signaling On binding of insulin to the alpha
Humoral: somatostatin
subunit, the beta subunit activates itself by autophosphorylation.
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Drugs: diazoxide, thiazides, β-blockers,

clonidine, phenytoin, vinblastine, The activated beta subunit then recruits additional proteins to the
colchicine complex and phosphorylates a network of intracellular substrates,
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including insulin receptor substrate-1 (IRS-1), insulin receptor

substrate-2 (IRS-2), and others (Figure 17–6). These activated
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substrates each lead to subsequent recruitment and activation of

Insulin Receptors and Insulin Action additional kinases, phosphatases, and other signaling molecules in
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Insulin action begins with the binding of insulin to a receptor on a complex pathway that generally contains two arms: the mito-
the surface of the target cell membrane. Most cells of the body genic pathway, which mediates the growth effects of insulin and
have specific cell surface insulin receptors. In fat, liver, and muscle the metabolic pathway, which regulates nutrient metabolism.
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Insulin
Glucose
Insulin α-Subunit
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receptor
β-Subunit
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PI4,5-P2 PI3,4,5-P3
TK
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SHC domain PDK

SOS GLUT 4- Glucose
GRB2 Pl3 containing
IRS 1,2,3,4 kinase vesicles
G-6-P
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PKB/AKT
Others?
Ras mTOR UDPG
up
MAP
kinase Protein GS
pathways synthesis Glycogen
–
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GSK3
GS
Nucleus P
at
Cross-talk
P90 RSK PP-1
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Growth/mitogenic
effects Metabolic effects
FIGURE 17–6 A simplified outline of insulin signaling. A minimal diagram of the mitogenic and metabolic arms of the insulin-signaling
pathway is shown. GLUT 4, glucose transporter 4; GRB2, growth factor receptor–binding protein 2; GS, glycogen synthase (P indicates the inac-
tive phosphorylated form); GSK3, glycogen synthase kinase 3; IRS, insulin receptor substrate (four different proteins); MAP kinase, mitogen-
activated protein kinase; mTOR, mammalian target of rapamycin; PDK, phospholipid-dependent kinase; PI3 kinase, phosphatidylinositol 3
kinase; PKB/AKT, protein kinase B/AKR mouse tumor 8 kinase; PP-1, glycogen-associated protein phosphatase-1; Ras, rat sarcoma protein; SHC,
Src and collagen homology protein; SOS, son-of-sevenless related protein; TK, tyrosine kinase.

In the metabolic signaling pathway, activation of phosphati- overlap in the tissue expression and gene targets of the three
dylinositol-3-kinase leads to the activation of serine/threonine PPARs, some general conclusions can be drawn about the func-
kinase AKT/PKB. AKT activation drives the movement of tion of each. PPARα regulates genes involved in fatty acid catabo-
GLUT 4–containing vesicles to the cell membrane, increases lism and gluconeogenesis and is most highly expressed in brown
glycogen and lipid synthesis, and stimulates protein synthesis fat, heart, liver, kidney, and intestine. PPARβ/δ is broadly
through the activation of mTOR. In the mitogenic signaling expressed and activates gene programs involved in fatty acid oxida-
pathway, activation of Ras initiates a cascade of activating phos- tion. PPARγ is most highly expressed in adipose tissue, intestine,
phorylations via the MAP kinase pathway, leading to cell growth and immune cells, but also at lower levels in many other tissues.
and proliferation. PPARγ drives white adipocyte differentiation and lipid storage
and inhibits production of many of the pro-resistance adipokines
Transcriptional regulation In addition, the insulin-signaling and pro-inflammatory cytokines in adipose tissue (see section on
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pathway regulates the activity of several nuclear transcription insulin resistance later). In macrophages, PPARγ acts to promote
factors that in turn control the expression of genes involved in their alternative activation to the anti-inflammatory M2 state,
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metabolism and growth. These include members of the forkhead rather than the pro-inflammatory M1 state.
family of transcription factors, including Foxo1, which is inacti- The PPARs bind to DNA as heterodimers with the 9-cis-retinoic
vated by phosphorylation by AKT downstream of insulin signal-
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acid receptor (RXR), and recruit a variety of coactivators and

ing. Foxo1 coordinates the expression of gene networks involved corepressors. PGC1α was originally identified as a coactivator
in nutrient metabolism in multiple tissues, generally activating
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interacting with PPARγ, but the interaction is not exclusive. On

genes involved in the response to fasting. In this process, Foxo1 different genes PPARγ works with different coactivators, and
works with several other transcriptional regulators including the PGC1α interacts with the other PPARs and many other tran-
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lipogenic transcription factor SREBP1c, members of the PPAR scription factors. In collaboration with a variety of different
family of nuclear receptors and the PPAR coactivator PGC1α transcription factors in various tissues, PGC1α orchestrates the
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(Figure 17–7). Foxo1 also inhibits β cell proliferation and expression of a set of genes involved in metabolism. PGC1α
survival. itself is highly regulated by several signaling pathways including
The three members of the PPAR family of nuclear hormone insulin signaling, which inhibits PGC1α activity via phosphory-
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receptors play pleiotropic roles in regulating genes involved in lation by AKT.

metabolism in many tissues. They may function as targets of insu- A number of natural and synthetic lipids and related com-
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lin signaling, modulators of insulin signaling, or both. Despite pounds can act as PPAR ligands, but the endogenous ligands act-
ing in vivo remain a mystery. The fibrate class of lipid-lowering
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drugs, used clinically to lower circulating triglyceride levels, act as

Insulin
PPARα ligands. The thiazolidinedione class of insulin-sensitizing
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drugs, used for the treatment of type 2 diabetes (discussed later),

β Cell act as PPARγ ligands.
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survival and
proliferation AKT
Deactivation of insulin signaling Once activated by bind-
ing to insulin, the insulin receptor and downstream signaling
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SREBP1c Foxo1 PGC1α cascades rapidly deactivate again by several mechanisms. Insulin
can simply disengage from the receptor, or the receptor can be inter-
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nalized and degraded. The receptor and its tyrosine-phosphorylated

substrates can be deactivated by specific protein tyrosine phospha-
ACC GK MTTP PEPCK
FAS LPK G6P tases such as PTP1b. In addition, inhibitory SOCS (suppressor of
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ACLY PDH cytokine signaling) proteins block interactions between the

phosphorylated receptor and interacting IRS proteins, direct
the ubiquitination and degradation of the IRS proteins, and ter-
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Lipogenesis Glycolysis VLDL Gluconeogenesis minate the activation of downstream components of the signaling
pathway. Finally, serine phosphorylation of the insulin receptor
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FIGURE 17–7 Regulation and function of Foxo1. The blue and its active substrates by several different serine/threonine
arrows indicate stimulation, and the red lines indicate inhibition. Pro-
kinases, including components of the insulin-signaling pathway
cesses activated by Foxo1 are labeled in blue, while the processes
inhibited by Foxo1 are shown in red. (ACC, acetyl-CoA carboxylase;
such as AKT, blocks insulin signaling. Many of these mechanisms
ACLY, ATP-citrate lyase; AKT, AKR mouse tumor 8 kinase; FAS, fatty may play a role in the development of insulin resistance (discussed
acid synthase; G6P, glucose-6-phosphatase; GK, glucokinase; LPK, later).
liver pyruvate kinase; MTTP, microsomal triglyceride transfer protein;
PDH, pyruvate dehydrogenase; PEPCK, phosphoenolpyruvate car-
Metabolic Effects of Insulin
boxykinase; PGC1α, peroxisome proliferator-activated receptor
gamma coactivator-1; SREBP1c, sterol regulatory element-binding The major function of insulin is to promote storage of ingested
protein 1c). nutrients. Although insulin directly or indirectly affects the

function of almost every tissue in the body, the discussion here TABLE 17–3 Endocrine effects of insulin.
will be limited to a brief overview of the effects of insulin on the
major tissues specialized for energy metabolism: liver, muscle, Tissue Effect of Insulin
adipose tissue, and brain. In addition, the paracrine effects of Liver Catabolic Pathways
insulin will be discussed briefly. Inhibits glycogen breakdown (inhibits glycogen
phosphorylase)
Inhibits conversion of fatty acids and amino acids
A. Paracrine effects The effects of the products of endocrine to keto acids
cells on surrounding cells are termed paracrine effects, in contrast Inhibits conversion of amino acids to glucose
to actions that take place at sites distant from the secreting cells, (gluconeogenesis)
which are termed endocrine effects (see Chapter 1). Paracrine effects Anabolic Pathways
Promotes glucose storage as glycogen
of the β and δ cells on the nearby α cells (see Figure 17–1) are of
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(induces glucokinase and glycogen synthase)

considerable importance in the endocrine pancreas. Insulin Increases triglyceride synthesis and VLDL formation
directly inhibits α cell secretion of glucagon. In addition, soma-
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Muscle Protein Synthesis

tostatin, which δ cells release in response to most of the same Increases amino acid transport
stimuli that provoke insulin release, also inhibits glucagon Increases ribosomal protein synthesis
Glycogen Synthesis
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secretion.
Increases glucose transport
Because glucose stimulates only β and δ cells (whose products Induces glycogen synthase
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then inhibit α cells) whereas amino acids stimulate glucagon as Inhibits glycogen phosphorylase
well as insulin, the type and amounts of islet hormones released Adipose Triglyceride Storage
during a meal depend on the ratio of ingested carbohydrate to Tissue Lipoprotein lipase is induced by insulin to hydrolyze
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triglycerides in circulating lipoproteins for delivery

protein. The higher the carbohydrate content of a meal, the lower
of fatty acids to the adipocytes
the amount of glucagon released by any amino acids absorbed. In Glucose transport into cell provides glycerol
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contrast, a predominantly protein meal results in relatively greater phosphate to permit esterification of fatty acids
glucagon secretion, because amino acids are less effective at stimu- supplied by lipoprotein transport
Intracellular lipase is inhibited by insulin
lating insulin release in the absence of concurrent hyperglycemia
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but are potent stimulators of α cells. Brain Decreased appetite

Increased energy expenditure
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B. Endocrine effects (Table 17–3)

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1. Liver—The first major organ reached by insulin via the blood-

stream is the liver. Insulin exerts its action on the liver in two
major ways: glucose indirectly produced via the liver from lactate gener-
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a. Insulin promotes anabolism—Insulin promotes glycogen ated by muscle.

synthesis and storage while inhibiting glycogen breakdown. 3. Adipose tissue—Fat, in the form of triglyceride, is the most
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These effects are mediated by changes in the activity of efficient means of storing energy. It provides 9 kcal/g of stored
enzymes in the glycogen synthesis pathway (discussed later). substrate, as opposed to the 4 kcal/g generally provided by
The liver has a maximum storage capacity of 100 to 110 g protein or carbohydrate. In the typical 70-kg man, the energy
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of glycogen, or approximately 440 kcal of energy. content of adipose tissue is about 100,000 kcal.
Insulin increases both protein and triglyceride synthesis Insulin acts to promote triglyceride storage in adipocytes by
up
and very low density lipoprotein (VLDL) formation by the a number of mechanisms. (1) It induces the production of
liver. It also inhibits gluconeogenesis and promotes glycoly- lipoprotein lipase in adipose tissue (this is the lipoprotein lipase
sis through its effects on the function and expression of key that is bound to endothelial cells in adipose tissue and other
enzymes of both pathways. vascular beds), which leads to hydrolysis of triglycerides from
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b. Insulin inhibits catabolism—Insulin acts to reverse the circulating lipoproteins, thereby yielding fatty acids for uptake
catabolic events of the postabsorptive state by inhibiting by adipocytes. (2) By increasing glucose transport into fat cells,
hepatic glycogenolysis, ketogenesis, and gluconeogenesis. insulin increases the availability of α-glycerol phosphate, a
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2. Muscle—Insulin promotes protein synthesis in muscle by substance used in the esterification of free fatty acids into tri-
increasing amino acid transport, as well as by stimulating glycerides. (3) Insulin inhibits intracellular lipolysis of stored
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ribosomal protein synthesis. In addition, insulin promotes triglyceride by inhibiting intracellular lipase (also called
glycogen synthesis to replace glycogen stores expended by hormone-sensitive lipase). This reduction of fatty acid flux to
muscle activity. This is accomplished by increasing glucose the liver is a key regulatory factor in the action of insulin to
transport into the muscle cell, enhancing the activity of gly- lower hepatic gluconeogenesis and ketogenesis.
cogen synthase, and inhibiting the activity of glycogen phos- 4. Central nervous system—Although the brain is traditionally
phorylase. Approximately 500 to 600 g of glycogen are stored not considered an insulin-sensitive tissue, and overall glucose
in the muscle tissue of a 70-kg man, but because of the lack utilization by the brain is not acutely regulated by insulin, key
of glucose 6-phosphatase in this tissue, it cannot be used as a regions of the brain can respond to insulin. Insulin signaling
source of blood glucose, except for a small amount produced via PI3 kinase in key cells in the hypothalamus functions with
when the debranching enzyme releases unphosphorylated leptin signaling to decrease appetite and increase energy expen-
glucose from branch points in the glycogen polymer, and the diture (see Chapter 20).

C. AMPK and insulin-independent regulation of nutri- While predominantly an intracellular energy sensor, AMPK
ent metabolism Insulin, along with the counter-regulatory increases the sensitivity of cells to insulin, although the mecha-
hormones and other circulating enhancers and inhibitors of their nisms remain uncertain. AMPK also responds to extracellular
actions, coordinates nutrient metabolism in response to the overall signals, and contributes to the regulation of metabolism by many
needs of the organism. At the level of the individual cell, however, of the adipokines and cytokines (discussed later) as well as can-
additional mechanisms sense and respond to the local energy state. nabinoids. The biguanide drugs, including metformin, which is
Among these mechanisms, adenosine monophosphate protein used in the treatment of type 2 diabetes, activate AMPK by reduc-
kinase (AMPK) plays a central role. When energy availability falls, ing mitochondrial production of ATP and raising intracellular
the drop in cellular ATP concentration and rise in AMP trigger a levels of AMP, and thereby lower blood glucose levels by inhibiting
conformational change in the trimeric AMPK complex and the gluconeogenesis.
subsequent activation of the catalytic domain by the serine/threonine
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kinase LBK1/STK11. AMPK then drives the production of ATP

Glucose Transporter Proteins
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by activating catabolic pathways and inhibiting synthetic path-

ways in the cell (Figure 17–8). In muscle, in response to the rise Glucose oxidation provides energy for most cells and is critical for
in AMP during exercise, AMPK increases fatty acid oxidation and brain function. Because cell membranes are impermeable to
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insulin-independent glucose uptake while inhibiting mTOR and hydrophilic molecules such as glucose, all cells require carrier pro-
protein synthesis. In the long term, AMPK also drives mitochon- teins to transport glucose across the lipid bilayers into the cytosol.
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drial biogenesis. In liver cells, AMPK blocks fatty acid and triglyc- All cells utilize non-energy-dependent transporters that facilitate
eride synthesis while activating fatty acid oxidation, and also diffusion of glucose from a higher concentration to a lower con-
inhibits the gluconeogenic program by blocking cAMP activation centration across cell membranes. Facilitative GLUTs comprise a
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of gene expression and inhibiting Foxo1/PGC1α-driven expres- large family including at least 13 members, although some of the
sion of the gluconeogenic genes. In brain, AMPK also functions recently identified members of the family have not yet been shown
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as an energy sensor and plays a role in the regulation of appetite to transport glucose. The first four members of the family are the
and energy expenditure by the hypothalamus. AMPK has also best characterized, and they have distinct affinities for glucose and
been implicated in the regulation of insulin secretion by β cells. distinct patterns of expression.
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Metformin
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Tak1
CamKK
LKB1
PKA AMP
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Insulin PP2C Adiponectin

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Resistin Fatty acids

AKT
AMPK
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Proliferation
Mitochondrial
TSC1/2 biosynthesis
up
mTOR SREBP1c MCD

TORC2
eEF2 GLUT4 ACC
PGC1α HMGR GPAT FAS
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HK
PFK2 Malonyl CoA
G6P
PEPCK
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Protein Cholesterol Triglyceride Fatty acid Fatty acid

synthesis Glycolysis Gluconeogenesis synthesis synthesis synthesis oxidation
↓Growth ↓Glucose production ↓Lipid synthesis
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↑Glucose utilization ↑Lipid oxidation
FIGURE 17–8 Regulation and function of AMPK. Proteins that are directly phosphorylated by AMPK are shown in bold font. The blue
arrows indicate stimulation, and the red lines indicate inhibition. Processes activated by AMPK are labeled in blue, while the processes inhibited
by AMPK are shown in red. (ACC, acetyl-CoA carboxylase; AKT, AKR mouse tumor 8 kinase; CamKK, calcium/calmodulin-dependent protein
kinase kinase; eEF2, eukaryotic translation elongation factor 2; FAS, fatty acid synthase; G6P, glucose-6-phosphatase; GPAT, glycerol-3-phosphate
acyltransferase, mitochondrial; HK, hexokinase; HMGR, HMG-CoA reductase; LKB1, liver kinase B1; MCD, malonyl-CoA decarboxylase; mTOR,
mammalian target of rapamycin; PEPCK, phosphoenolpyruvate carboxykinase; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase;
PGC1α, peroxisome proliferator-activated receptor gamma coactivator-1; PKA, protein kinase A; PP2C, protein phosphatase 2C; SREBP1c, sterol
regulatory element–binding protein 1c; Tak1, TGF-β-activated kinase 1; TORC2, transducer of regulated cAMP response element-binding protein
2; TSC1/2, tuberous sclerosis 1).

GLUT 1 is present in all human tissues. It mediates basal glu- 2. GLUCAGON

cose uptake, because it has a very high affinity for glucose and,
therefore, can transport glucose at the relatively low concentra- Biochemistry
tions found in the fasted state. For this reason, its presence on the Pancreatic glucagon, along with several other biologically active
surface of the endothelial cells of the brain vascular system peptides, derives from the large proglucagon peptide encoded by
(blood–brain barrier) ensures adequate transport of plasma glu- the preproglucagon gene located on human chromosome 2. Tis-
cose into the central nervous system. sue-specific proteases (the prohormone convertases) cleave differ-
GLUT 3, which is also found in all tissues, is the major GLUT ent sets of peptide products from the proglucagon molecule in the
on neurons. It also has a very high affinity for glucose and is endocrine l-cells of the gut and the α cells in the islet (Figure
responsible for transferring glucose into neuronal cells at the lower 17–9). The activity of prohormone convertase 2 in α cells gener-
concentrations found in the central nervous system.
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ates the glucagon peptide, along with the amino-terminal glicen-

In contrast, GLUT 2 has a lower affinity for glucose and thus tin-related peptide, a small central hexapeptide, and a large
increases glucose transport when plasma glucose levels rise, such as
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carboxyl-terminal fragment.
postprandially. It is a major transporter of glucose in hepatic, Glucagon consists of 29 amino acids in a single-chain polypep-
intestinal, and renal tubular cells. The low affinity of GLUT 2 for tide with a molecular weight of 3485. In healthy humans, the
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glucose reduces hepatic uptake of glucose during fasting, while its average fasting plasma immunoreactive glucagon level is 75 pg/mL
ability to transport glucose equally efficiently in both directions (25 pmol/L). Only 30% to 40% of this is actually pancreatic glu-
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assists in the export of glucose from hepatocytes. GLUT 2 is also cagon, the remainder being a heterogeneous composite of higher-
expressed on the surface of the β cells in rodents, but it is not molecular-weight molecules with glucagon immunoreactivity
detected at significant levels on human β cells. such as proglucagon, glicentin, and oxyntomodulin. Circulating
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GLUT 4 is found in two major insulin target tissues: skeletal glucagon has a half-life of 3 to 6 minutes due to removal by the
muscle and adipose tissue. It is sequestered mainly within an intra- liver and kidney.
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cellular compartment of these cells and thus does not function as a

GLUT until insulin signaling causes translocation of GLUT 4 to
the cell membrane, where it facilitates glucose entry into these tis- Secretion
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sues after a meal (see Figure 17–6). In muscle, exercise also drives In contrast to its stimulation of insulin secretion, glucose inhibits
GLUT 4 translocation to the cell surface by activating AMPK. glucagon secretion. Conflicting data surround the question of
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The intestine and kidney also have energy-dependent Na+- whether glucose directly inhibits secretion from the α cell or
glucose cotransporters capable of transporting glucose against its whether it only acts via release of insulin and somatostatin from
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concentration gradient. SGLT1 transports glucose from the gut the β and δ cells, both of which inhibit the α cell directly. In addi-
lumen into the absorptive enterocytes lining the lumen and is also tion, because β cells release gamma-aminobutyric acid (GABA)
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found in the proximal tubules of the kidney. SGLT2, however, and α cells express inhibitory GABA receptors, GABA also may
which is found in the proximal convoluted tubules in the kidney, participate in the inhibition of α cells during β cell stimulation.
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performs the majority of the renal glucose reabsorption. Many amino acids stimulate glucagon release, although they
differ in their ability to do so. Some, such as arginine, release both
Islet Amyloid Polypeptide glucagon and insulin; others (eg, alanine) stimulate primarily glu-
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cagon release. Leucine, an effective stimulant of insulin release,

Islet amyloid polypeptide (IAPP), or amylin, is a 37 amino acid does not stimulate glucagon. Other substances that promote glu-
peptide produced and stored with insulin in pancreatic β cells but
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cagon release include catecholamines, gastrointestinal hormones

only at a low ratio of approximately one molecule of IAPP to 100 (cholecystokinin [CCK], gastrin, and gastric inhibitory polypep-
of insulin. β cells cosecrete IAPP with insulin in response to glutide [GIP]), and glucocorticoids. Both sympathetic and parasym-
cose and other β cell secretagogues. Although it plays a role in
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pathetic (vagal) stimulation promote glucagon release, especially

regulating gut physiology by decreasing gastric emptying and gut in response to hypoglycemia. High levels of circulating fatty acids
motility after meals, the full physiologic functions of IAPP remain suppress glucagon secretion.
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uncertain. A soluble analog of IAPP called pramlintide has been

approved for use in patients with type 1 diabetes and insulin-
Action of Glucagon
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treated type 2 diabetes (discussed later).

IAPP produces amyloid deposits in pancreatic islets of most In contrast to insulin, which promotes energy storage in a variety
patients with type 2 diabetes of long duration. These amyloid of tissues in response to feeding, glucagon provides a humoral
deposits are insoluble fibrillar proteins generated from IAPP oligo- mechanism for delivering energy from the liver to the other tissues
mers that encroach on and may even occur within pancreatic β cells. between meals. The ratio of insulin to glucagon affects key target
Islets of nondiabetic elderly persons may contain less extensive tissues by regulating the expression and activity of key enzymes
amyloid deposits. Whether amyloid fibrils and deposition contrib- controlling nutrient metabolism and, thereby, controlling the flux
ute to the islet dysfunction and β cell loss seen in type 2 diabetes of these nutrients into or out of storage.
or are simply a consequence of disordered and hyperstimulated The liver, because of its connection to the pancreas via the
islet function remains an unresolved question. portal vein, represents the major target organ for glucagon, with

Glicentin-
Human related Glucagon GLP-1 GLP-2
proglucagon polypeptide
1 33 61 69 72 108 126 160
Hexa-
Pancreas GRPP Glucagon pep- Major proglucagon fragment
α cell tide
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Small Truncated
Glicentin GLP-2
intestine GLP-1 (7-37)
69
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GRPP Oxyntomodulin
1 30 33 69
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FIGURE 17–9 Tissue-specific secretory products of human proglucagon (GLP-1, glucagon-like peptide-1; GLP-2, glucagon-like peptide-2;
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GRPP, glicentin-related polypeptide).
portal vein glucagon concentrations reaching as high as 300 to interactions with the receptors for glucagon, GLP-1 and GLP-2.
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500 pg/mL (100-166 pmol/L) during fasting. It is unclear Specific receptors for glicentin and oxyntomodulin have not been
whether physiologic levels of glucagon affect tissues other than the identified, and it remains uncertain whether these peptides play
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liver. Glucagon signals through the glucagon receptor, a GPCR of any biological role at physiologic concentrations. GRPP also has
the Gαs class found predominantly on the surface of hepatocytes. no clearly established biological activity. The other two gut-
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Binding of glucagon to its receptor in the liver activates adenylyl derived glucagon-related peptides, GLP-1 and GLP-2, however,
cyclase and the generation of cAMP, which in turn mediates the play important roles in nutrient metabolism and gastrointestinal
phosphorylation or dephosphorylation of key enzymes regulating physiology (Table 17–4).
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nutrient metabolism. In addition, like insulin, glucagon receptor There are two active forms of GLP-1: GLP-1(7-36) amide, and
signaling modifies the activity of a set of cAMP responsive tran- GLP-1(7-37). The intestinal l-cells secrete GLP-1 in response to
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scriptional regulators that in turn control the expression of the meals, through dietary glucose and lipids and parasympathetic
genes encoding these same enzymes. stimulation. The l-cells sense dietary fat in the gut lumen in part
Glucagon signaling in the liver stimulates the breakdown of through the GPR119 receptor, which binds the long chain fatty
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stored glycogen, maintains hepatic output of glucose from amino acid derivative oleoylethanolamide. GPR119 is also expressed on
the surface of the β cells. GLP-1 binds to the GLP-1 receptor, a
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acid precursors (gluconeogenesis), and promotes hepatic output of

ketones generated from fatty acid precursors (ketogenesis). Gluca- GPCR similar to the glucagon receptor. The ubiquitous protease
gon facilitates the uptake of the gluconeogenic substrate alanine dipeptidyl peptidase 4 (DPP-4) rapidly inactivates circulating
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by liver, and directs fatty acids away from reesterification to tri- GLP-1 (half-life <2 min) by removing the two amino-terminal
glycerides and toward ketogenic pathways. In sum, glucagon sig- amino acids. Pancreatic islets are major targets of GLP-1 action.
naling results in the net release of readily available energy stores GLP-1 directly stimulates the production and secretion of insulin
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from the liver in the form of glucose and ketones. and somatostatin, and thereby indirectly inhibits the secretion of
glucagon. In addition, GLP-1 protects the β cells from destruction
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and stimulates β cell growth. Other targets of GLP-1 include the

Glucagon-Related Peptides stomach, where the peptide inhibits gastric emptying and gastric
In the intestinal l-cells, found predominantly in the distal ileum acid secretion; the brain, where it inhibits appetite and induces
and colon, prohormone convertase 1 generates a different set of weight loss; and the heart, where it has some protective effects.
peptides from the proglucagon molecule, including glicentin, gli- Along with GLP-1, intestinal l-cells cosecrete GLP-2 in
centin-related polypeptide (GRPP), oxyntomodulin, and the two response to eating; and like GLP-1, GLP-2 binds to a specific
glucagon-like peptides GLP-1 and GLP-2 (see Figure 17–9). GPCR closely related to the glucagon and GLP-1 receptors.
Several biological activities have been attributed to glicentin and DPP-4 also inactivates GLP-2. GLP-2 signaling predominantly
oxyntomodulin based on studies using high concentrations of the targets the intestine, where it stimulates mucosal growth and
peptides, but all these actions can be explained by low-affinity nutrient absorption and inhibits motility.

TABLE 17–4 Biologic roles of glucagon-related peptides.

Target Tissue Glucagon GLP-1 GLP-2 GIP
Islet Stimulates insulin secretion Stimulates insulin and soma- Stimulates insulin, somatosta-
tostatin secretion tin, and glucagon secretion
Inhibits glucagon secretion Inhibits glucagon secretion
(indirectly) (indirectly)
Inhibits β cell death Inhibits β cell death
Liver Stimulates glycogenolysis,
gluconeogenesis, fatty acid
oxidation, and ketogenesis
Inhibits glycogen synthesis
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and fatty acid synthesis

Inhibits gastric acid secretion Inhibits gastric acid secretion
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Stomach
Inhibits gastric emptying and gastric emptying
Intestine Stimulates mucosal Stimulates GLP-1 secretion by
growth and nutri- l-cells
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ent absorption
Inhibits motility
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Adipose tissue Stimulates adipogenesis,

lipogenesis, and adipokine
production
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Brain Inhibits appetite

(hypothalamus)
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The K cells in the duodenum and jejunum produce a related through its stimulation of insulin secretion. The GIP receptor is
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42 amino acid incretin peptide, GIP, that has both functional and also expressed in adipose tissue and bone. In adipose tissue, GIP
sequential similarity to GLP-1, but is the product of a distinct plays an important role in the differentiation of new adipocytes,
gene and binds to a distinct receptor, GIPR, which also belongs to and also drives lipogenesis and adipokine production in mature
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the family of glucagon-related Gαs-linked receptors. The K cells adipocytes. In bone, GIP stimulates the osteoblasts and increases
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secrete GIP in response to glucose—via the same pathway used by bone density.
the β cell (see Figure 17–5)—and lipids. Interestingly, the GIP
prepropeptide is also expressed in α cells, but prohormone conver-
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tase 2 in α cells produces a shorter peptide, GIP1-30, which lacks 3. SOMATOSTATIN

the 12 carboxyl amino acids present in intestinal GIP1-42. The two The pancreatic δ cells transcribe the gene for somatostatin on the
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forms of GIP appear to function identically. GIP signaling long arm of chromosome 3. It codes for a 116 amino acid peptide,
through its receptor has similar effects to those of GLP-1 on the preprosomatostatin, from whose carboxyl end is cleaved the hor-
stomach and β cells. α Cells also express the GIP receptor, mone somatostatin, a 14 amino acid cyclic polypeptide with a
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through which GIP directly stimulates glucagon secretion; but molecular weight of 1640 (Figure 17–10). First identified in the
GIP concomitantly suppresses glucagon secretion indirectly hypothalamus, it owes its name to its ability to inhibit the release
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Preprosomatostatin (116 AA)

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1 12 13 14 15 28
–
-COOH
at
NH2 ARG ARG-LYS SOMATOSTATIN-14

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Prosomatostatin (28 AA)

(Somatostatin-28)
Somatostatin (14 AA)
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys
1 14
FIGURE 17–10 Amino acid sequence of somatostatin and its cleavage from dibasic amino acid residue in prosomatostatin and
preprosomatostatin.

of growth hormone (GH; pituitary somatotropin). Since that that is cleaved to a single 36 amino acid peptide with a molecular
time, somatostatin has been found in a number of tissues, includ- weight of 4200. Circulating levels of the peptide increase in
ing many areas of the brain and peripheral nervous system, the response to a mixed meal; however, intravenous infusion of glu-
endocrine D cells in the epithelial lining of the stomach and intes- cose or lipid does not produce such a rise, and intravenous
tine, and the δ cells in the pancreatic islets. In neurons, gastric D cells amino acids induce only a small increase. In contrast, vagotomy
and the islet, somatostatin-14 predominates, but approximately abolishes the response to an ingested meal, demonstrating that
5% to 10% of the somatostatin-like immunoreactivity in the PP secretion responds predominantly to neural, rather than
brain consists of a 28 amino acid peptide, somatostatin-28. Soma- nutrient signals.
tostatin-28 consists of an amino terminal region of 14 amino acids In healthy subjects, basal levels of PP average 24 ± 4 pmol/L
and a carboxyl terminal segment containing somatostatin-14. In and may become elevated owing to a variety of factors including
small intestine, the larger molecule predominates, with 70% to old age, alcohol abuse, diarrhea, chronic renal failure, hypoglyce-
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75% of the hormone in the 28 amino acid form and only 25% to mia, or inflammatory disorders. Values above 300 pmol/L are
30% as somatostatin-14. Somatostatin-28 is 10 times more potent found in most patients with pancreatic endocrine tumors such as
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than somatostatin-14 in inhibiting growth hormone and insulin glucagonoma or vasoactive intestinal polypeptide-secreting tumor
secretion, whereas somatostatin-14 is more effective in inhibiting and in all patients with tumors of the pancreatic PP cell. As many
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glucagon release. as 20% of patients with insulinoma and one-third of those with
Most known stimulators of insulin release also promote soma- gastrinomas also have plasma concentrations of PP that are greater
tostatin release from δ cells. These include glucose, arginine, gas-
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than 300 pmol/L.

trointestinal hormones, and sulfonylureas. The peptide hormone Although it has been implicated in the regulation of exocrine
Urocortin3 (Ucn3), which is secreted by the b cells, also stimulates pancreatic secretion and gall bladder contraction, the physiologic
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somatostatin secretion. The importance of circulating somatosta- actions of PP remain uncertain.

tin is unclear; the major action of this peptide appears to be para-
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crine regulation of the pancreatic islet and the gastrointestinal 5. GHRELIN

tract. Physiologic levels of somatostatin in humans seldom exceed
80 pg/mL (49 pmol/L). The metabolic clearance of exogenously The peptide hormone ghrelin was originally identified in extracts
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infused somatostatin in humans is extremely rapid; the half-life of from the stomach based on its ability to bind to and activate the
the hormone is less than 3 minutes. growth hormone secretagogue receptor (GHSR) and stimulate
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Molecular cloning has identified five somatostatin receptors growth hormone release from the pituitary (thus the basis of its
(SSTR1-5), all of which are GPCRs. They vary in size from 364 name: growth hormone-releasing peptide). The P/D1 endocrine
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to 418 amino acids (with 105 amino acids invariant) and function cells in the gastric mucosa and the ε cells in the islet make ghrelin,
in the central nervous system and a wide variety of peripheral tis- as do a few cells in the heart, lung, kidney, immune system, hypo-
thalamus, and pituitary. The human GHRELIN gene comprises
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sues, including the pituitary gland, the small intestine, and the
pancreas. All five receptors belong to the Gαi class and inhibit the four exons, and the major splice product encodes the 117 amino
acid preproghrelin peptide. Processing in the ε cells yields the
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activity of adenylate cyclase, thereby lowering intracellular levels

of cAMP and inhibiting cAMP-activated secretion. In addition, active form of ghrelin: a 28 amino acid peptide (amino acids
however, each of the different somatostatin receptors interacts 24-51 of preproghrelin) with the serine in position 3 modified by
the attachment of an octanoyl side chain by Ghrelin O-acyltrans-
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with additional distinct downstream effectors that modify the cel-

lular consequences of receptor activation. Binding of ligand to ferase (GOAT). Full biological activity requires the n-octanoyl
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SSTR5 on β cells mediates the inhibition of insulin secretion, modification. In addition, protease cleavage generates a second
whereas inhibition of GH release from pituitary somatotrophs as peptide, obestatin (amino acids 76-98 of preproghrelin) of less
well as glucagon release from α cells of the pancreas works through certain biological function.
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SSTR2. This explains why an analog of somatostatin, octreotide, Initially identified as a stimulator of growth hormone secre-
which has a much greater affinity for SSTR2 than for SSTR5, is tion, ghrelin signals through its receptor, the previously identified
effective in correcting GH excess without having much effect on GHSR, which is a GPCR found in a variety of tissues, including
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carbohydrate tolerance when used to treat acromegaly. the hypothalamus, pituitary, intestine, and islet. Ghrelin signaling
Somatostatin acts in several ways to restrain the movement of stimulates growth hormone secretion directly through its receptor
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nutrients from the intestinal tract into the circulation. It prolongs on pituitary somatotrophs, and also through its stimulation of
gastric emptying time, decreases gastric acid and gastrin produc- hypothalamic GHRH secretion. In addition, ghrelin induces gas-
tion, diminishes pancreatic exocrine secretion, decreases splanch- tric emptying and acid secretion and regulates appetite and energy
nic blood flow, and retards xylose absorption. balance via neurons in the arcuate nucleus of the hypothalamus
(see Chapter 20). Recent evidence from rodents suggests that
ghrelin plays an essential role in conserving energy and maintain-
4. PANCREATIC POLYPEPTIDE ing blood glucose levels during starvation. The role of ghrelin
PP is found in PP cells located chiefly in islets in the posterior signaling in the pancreas, and the relative contribution of islet-
portion of the head of the pancreas. Similar to the other islet derived ghrelin to the overall actions of ghrelin remains
hormones, PP derives from a larger prepropeptide of 85 amino acids unresolved.

DIABETES MELLITUS or non-insulin-dependent diabetes mellitus [NIDDM]), the most

prevalent form of diabetes, is a heterogeneous disorder most com-
Clinical diabetes mellitus is a syndrome of disordered metabolism monly associated with insulin resistance combined with an impair-
with inappropriate hyperglycemia due to an absolute or relative ment in compensatory insulin secretion.
deficiency of insulin. There may also be a defect in insulin action
(insulin resistance).
TYPE 1 DIABETES MELLITUS
CLASSIFICATION Type 1 diabetes is immune-mediated in more than 95% of cases
(type 1a) and idiopathic in less than 5% (type 1b). The rate of
Diabetes is classified into five main groups based on known patho- pancreatic β cell destruction may vary, but in most cases the pro-
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logical and etiologic mechanisms—type 1, type 2, monogenic, cess is prolonged, extending over months or years, since evidence
secondary, and gestational diabetes (Table 17–5). Type 1 diabetes for an immune response can be detected long in advance of hyper-
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(previously referred to as juvenile-onset or insulin dependent dia- glycemia in patients that eventually develop type 1 diabetes. It is a
betes mellitus [IDDM]) results from pancreatic islet β cell catabolic disorder in which circulating insulin is virtually absent,
destruction most commonly by an autoimmune process. These plasma glucagon is elevated, and the pancreatic β cells fail to
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patients are prone to developing ketoacidosis and require insulin respond to all known insulinogenic stimuli. In the absence of
replacement. Type 2 diabetes (previously referred to as adult-onset insulin, the three main target tissues of insulin (liver, muscle, and fat)
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TABLE 17–5 Etiologic classification of diabetes mellitus.

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I. Type 1 Diabetesa (β cell destruction, usually leading to absolute IV. Secondary Diabetes
insulin deficiency) A. Diseases of the exocrine pancreas
A. Immune-mediated, type 1a 1. Pancreatitis
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B. Idiopathic, type 1b 2. Trauma, pancreatectomy

3. Neoplasia
II. Type 2 Diabetesa (may range from predominantly insulin
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4. Cystic fibrosis

resistance with relative insulin deficiency to a predominantly
5. Hemochromatosis
secretory defect with minimal insulin resistance)
6. Fibrocalculous pancreatopathy
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III. Monogenic Diabetes B. Endocrinopathies

A. Autosomal dominant genetic defects of pancreatic β cells 1. Acromegaly
1. Maturity onset diabetes of the young (MODY) 2. Cushing syndrome
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2. Insulin gene (INS) 3. Glucagonoma

3. ATP-sensitive potassium channel (KCNJ11 and ABCC8) 4. Pheochromocytoma
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B. Other genetic defects of pancreatic β cells 5. Hyperthyroidism

1. Autosomal recessive genetic defects 6. Somatostatinoma
2. Mitochondrial DNA 7. Aldosteronoma
3. Ketosis-prone diabetes (KPD) C. Drug- or chemical-induced
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C. Genetic defects in insulin action 1. β cell toxicity: vacor, pentamidine, cyclosporine
1. Insulin receptor mutations 2. β cell autoimmunity: α-interferon, anti-PD-1, anti-PD-L1,
2. Lipoatrophic diabetes
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anti-CTLA-4
D. Neonatal diabetes (overlaps with categories A, B, C, E, and F) 3. β cell dysfunction: thiazide and loop diuretics, diazoxide, α
1. Transient agonists, β blockers, phenytoin, opiates
2. Permanent 4. Insulin resistance: glucocorticoids, progesterone, nicotinic
lic
E. Monogenic autoimmune syndromes acid, thyroid hormone, β blockers, atypical antipsychotic
1. IPEX: Immunodysregulation polyendocrinopathy drugs, antiretroviral protease inhibitors
enteropathy, X-linked D. Infections
2. Autoimmune polyendocrinopathy syndrome type 1
at
1. Congenital rubella

3. Other autosomal recessive autoimmune polyendocrinopa- 2. Other viruses: cytomegalovirus, coxsackievirus B,
thies (IL2RA, ITCH, and LRBA) adenovirus, mumps
e
4. Other autosomal dominant autoimmune polyendocrinopa- E. Uncommon forms of immune-mediated diabetes
thies (STAT1, STAT3, and SIRT1) 1. Stiff-person syndrome
F. Other genetic syndromes sometimes associated with diabetes 2. Anti-insulin receptor antibodies
1. Chromosomal defects: Down, Klinefelter, and Turner 3. POEMS syndrome
syndromes
V. Gestational Diabetes Mellitus (GDM)
2. Neuromuscular syndromes: Friedreich ataxia, Huntington
chorea, myotonic dystrophy, porphyria, and others
3. Obesity syndromes: Laurence-Moon-Biedl, Bardet-Biedl,
Prader-Willi syndromes, and others
4. Wolfram syndrome
a
Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient.
Data from American Diabetes Association. Classification and Diagnosis of Diabetes. Diabetes Care. 2016 Jan;39 Suppl 1:S13-22.

not only fail to appropriately take up absorbed nutrients but con- TABLE 17–6 Diagnostic sensitivity and specificity of
tinue to deliver glucose, amino acids, and fatty acids into the autoimmune markers in newly
bloodstream from their respective storage depots. Furthermore, diagnosed patients with type 1
alterations in fat metabolism lead to the production and accumu- diabetes mellitus.
lation of ketones. This inappropriate persistence of the fasted state
Sensitivity (%) Specificity (%)
postprandially can be reversed by the administration of insulin.
The incidence of type 1 diabetes varies widely in different Glutamic acid decarboxylase 70-90 99
populations. Scandinavia and northern Europe have the highest (GAD65)
incidence of type 1 diabetes: the yearly incidence per 100,000 Insulin (IAA) 40-70 99
youngsters 14 years of age or less is as high as 40 in Finland, 31 in Tyrosine phosphatase IA2 50-70 99
Sweden, 22 in Norway, 27 in Scotland, and 20 in England. The (ICA512)
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incidence of type 1 diabetes generally decreases across the rest of Zinc transporter 8 (ZnT8) 50-70 99
Europe to 11 in Greece and 9 in France. Surprisingly, the island
ev
of Sardinia has as high an incidence as Finland, even though in the

rest of Italy, including the island of Sicily, the incidence is only 11
destruction of β cells in type 1 diabetes. Instead, it is the cellular
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per 100,000 per year. The United States averages 16 per 100,000.
The lowest incidence of type 1 diabetes worldwide is less than 1 immune system, the T lymphocytes that infiltrate the islets (a
process called insulitis) and destroy the β cells. At the time of
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per 100,000 per year in China and parts of South America.

Worldwide incidence of type 1 diabetes continues to increase diagnosis, the islets of patients with type 1 diabetes are extensively
steadily. In Finland, the incidence has more than tripled since infiltrated with T lymphocytes.
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1953, when it was 12/100,000/year, with an average increase of Normally, the thymus deletes autoreactive T cells during devel-
2.4% per year. The EURODIAB study group reported recently opment so that the immune system becomes tolerant of self-
op
0.6% to 9.3% annual increases in incidence of type 1 diabetes in antigens. In addition, certain specialized T cells, the regulatory
children younger than 15 years in various European countries. T cells, further prevent attacks against healthy tissues by restrain-
The most rapid increases have occurred in low-prevalence coun- ing the activity of any autoreactive T cells that escape the thymus.
y
tries and in younger patients. Changes in environmental factors Type 1 diabetes results from a breakdown in these processes of
most likely explain this increased incidence. self-tolerance in the immune system.
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Latent autoimmune diabetes of adulthood (LADA) Type 1 Type 1b diabetes Approximately 5% of patients with the
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diabetes can present at any age, although peaks in incidence occur clinical features of type 1 diabetes lack serum evidence of auto-
before school age and around puberty. Older adults often present immunity. Some of these individuals have high-risk HLA haplo-
with a more indolent onset that sometimes leads to misdiagnosis types (discussed later) and may have T-cell–mediated β cell
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and has led to the use of the term latent autoimmune diabetes of destruction in the absence of measurable levels of the known
autoantibodies. Others in this group have low-risk HLA haplo-
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adulthood (LADA) to distinguish these patients. These initially

unrecognized patients may retain enough β cell function at the types, and appear to have a nonautoimmune cause for loss of β cell
outset to avoid ketosis, but develop increasing dependence on function. Such nonautoimmune type 1 diabetes has been referred
insulin therapy over time as their β cell mass diminishes. Islet cell to as type 1b diabetes, but a variety of terms has been used. This
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antibody surveys among northern Europeans indicate that up to probably represents a heterogeneous group of disorders that lead
to profound β cell dysfunction or loss, absolute insulin deficiency
up
15% of patients previously diagnosed with type 2 diabetes may

actually have LADA. and a syndrome clinically similar to autoimmune type 1a diabetes.
Under the accepted classification system, as specific disorders
within this subgroup become defined and the genetic or environ-
lic
Autoimmunity and Type 1 Diabetes mental causes are identified, these disorders become reclassified
Most patients with type 1 diabetes at diagnosis have circulating within the monogenic or secondary forms of diabetes.
at
antibodies against β cell proteins: islet cell antibodies (ICA), insulin Included within this group are patients that present with a
autoantibodies (IAA), and antibodies to glutamic acid decarboxyl- course of relapsing diabetic ketoacidosis with intervening normo-
e
ase 65 (GAD), tyrosine phosphatase IA2 (ICA512), and zinc trans- glycemia that eventually progresses to permanent insulin-deficient
porter 8 (ZnT8) (Table 17–6). These autoreative antibodies can diabetes. This disorder, ketosis prone diabetes (KPD, discussed
often be detected well before the onset of frank hyperglycemia, even later), has also been referred to as type 1b diabetes, and may result
decades earlier, providing evidence that the autoimmune process from unknown environmental insults combined with genetic
may be prolonged. After diagnosis, autoantibody levels often defects in the β cell.
decline with increasing duration of the disease. Also, once patients
are treated with insulin, low levels of IAA develop, even in patients Autoimmune diabetes and stiff person syndrome GAD
that do not have an autoimmune etiology for their diabetes. antibodies, the first identified in type 1 diabetes, remain among
Although useful for diagnosing and predicting type 1 diabetes, the most clinically useful. Human pancreatic β cells produce
antibodies against β cell proteins do not directly cause the GAD65, which functions as an enzyme that catalyzes the synthesis

of GABA from glutamate. GAD65 and the closely related isoform DQA1*0501, DQB1*0201 (coupled with DR3), and DQA1*0301,
GAD67 are also found in central nervous system inhibitory neu- DQB1*0302 (coupled with DR4). DQ alleles are associated not
rons that secrete GABA. Some patients with GAD antibodies only with risk for type 1 diabetes but also with dominant protec-
develop a rare neurologic condition, stiff person syndrome, tion, often in linkage with HLA-DR2. The most protective of
caused by the depletion of GABA in the central nervous system these—and a quite common allele—is DQA1*0102, DQB1*0602.
and characterized by progressive rigidity and fluctuating muscle It occurs in over 20% of individuals in the United States but in
spasms. Approximately half of the patients with stiff person syn- less than 1% of children who develop type 1 diabetes.
drome develop type 1 diabetes. An independent genetic link to chromosome 11 has also been
The vast majority of patients with type 1 diabetes do not identified in type 1 diabetes. Studies of a polymorphic DNA locus
develop symptoms of stiff person syndrome, despite the presence flanking the 5′ region of the insulin gene on chromosome 11
revealed a small but statistically significant linkage between type 1
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of GAD antibodies. The rare patients that develop the syndrome

usually have much higher titers of GAD antibodies than typical diabetes and this genetic locus in a Caucasian population with
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patients with type 1 diabetes alone. type 1 diabetes. This polymorphic locus, which consists of a vari-
able number of tandem repeats (VNTRs) with two common sizes
Genetics of Type 1 Diabetes in Caucasians, small (26-63 repeats) or large (140-243 repeats),
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does not encode a protein. An intriguing proposal to explain how

Family members of patients with type 1 diabetes have an increased the VNTR might influence susceptibility to type 1 diabetes was
lifetime risk of developing type 1 diabetes. The offspring of a
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based on findings that insulin gene transcription is facilitated in

mother with type 1 diabetes have a risk of 3%, whereas the risk is the fetal thymus gland by the presence of the large allele of the
6% for children of affected fathers. The risk in siblings of affected VNTR locus flanking the insulin gene. The large VNTR allele
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individuals is related to the number of human leukocyte antigen might produce a dominant protective effect by promoting negative
(HLA) haplotypes (discussed later) that the sibling shares. If one selection (deletion) by the thymus of insulin-specific T lymphocytes
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haplotype is shared, the risk is 6% and if two haplotypes are that play a critical role in the immune destruction of pancreatic
shared, the risk increases to 12% to 25%. For monozygotic twins, β cells.
the concordance rate reaches 25% to 50%. Although these data The established genetic association with the MHC region of
y
demonstrate a strong genetic contribution to the risk of type 1 chromosome 6 contributes much more (about 50%) to the genetic
diabetes, genetics plays an even larger role in type 2 diabetes, and susceptibility to type 1 diabetes than does this locus flanking the
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environment also clearly contributes substantially to the risk of insulin gene on chromosome 11, which contributes about 10%.
type 1 diabetes. Both candidate gene studies and genome-wide association studies
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Genes in the major histocompatibility (MHC) locus on the (GWAS) have identified a number of additional risk loci that make
short arm of chromosome 6 explain at least half of the familial smaller contributions to the genetic risk of type 1 diabetes. Many of
aggregation of type 1 diabetes. Within the MHC locus lie a num-
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the genes linked to these additional loci also play important roles in
ber of closely packed genes involved in the function and regula- the function and regulation of the immune response.
tion of the immune response. Although a number of genes within
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Mutations in two genes involved in T-cell tolerance cause rare

the MHC locus have been linked to the risk of developing type 1 syndromes of monogenic autoimmune diabetes together with
diabetes, the most important of these are the genes encoding the other autoimmune diseases. In the autosomal recessive disease
HLA class II molecules DQ and DR. The professional antigen-
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autoimmune polyglandular syndrome type 1 (APS1; see Chapter 2),

presenting cells—dendritic cells, macrophages and B lymphocytes— homozygous mutations in the gene encoding the autoimmune
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use the class II molecules on their cell surface to present peptide regulator (AIRE) prevent the expression of certain self-proteins in
antigens to T lymphocytes through the T-cell receptor. T cells the thymus, thus allowing mature autoreactive T cells to leave the
activated by antigen-presenting cells carry out the β cell destruc- thymus. In addition to other autoimmune diseases and mucocu-
lic
tion that leads to type 1 diabetes. Although exact mechanisms taneous candidiasis, approximately 20% of patients with APS1
remain uncertain, the variations in the amino acid sequence of develop type 1 diabetes. The second gene, FOXP3, found on the
individual HLA class II molecules may impact their ability to X chromosome, encodes a transcription factor required for the
at
present specific self-peptides to T cells either in the process of formation of regulatory T cells. Mutations in FOXP3 cause immu-
central or peripheral tolerization or later during the development nodysregulation polyendocrinopathy enteropathy X-linked
e
of the autoimmune response, thereby contributing to the risk of (IPEX) syndrome. IPEX presents in male patients with very early
developing type 1 diabetes. onset type 1 diabetes, often neonatal, combined with other auto-
The DR haplotypes DR3 and DR4 are major susceptibility immune endocrinopathies, autoimmune skin disorders, diarrhea
risk factors for type 1 diabetes. As many as 95% of type 1 diabetic secondary to autoimmune enteropathy, and frequent severe
patients have a DR3 or a DR4 haplotype—or both—compared infections.
with 45% to 50% of Caucasian nondiabetic controls. Individuals
who express both a DR3 and a DR4 allele carry the highest risk
for type 1 diabetes in the United States. Environmental Factors in Type 1 Diabetes
The high-risk DR genes are generally in linkage disequilibrium While genetic inheritance may play an important role in causing
with DQ genes that themselves confer high risk, particularly type 1 diabetes, the monozygotic twin studies demonstrate that

other causes, stochastic or environmental, are at least as important. TABLE 17–7 Factors reducing sensitivity to insulin.
Most individuals with type 1 diabetes do not have other family
members with the disease. Environmental factors associated with Prereceptor Insulin autoantibodies
Reduced transendothelial transit
increased risk of type 1 diabetes include viruses (mumps, congeni-
tal rubella, Coxsackie virus B4), toxic chemical agents such as vacor Primary defect in insulin Insulin receptor mutations
signaling Leprechaunism (complete)
(a nitrophenylurea rat poison), and other destructive cytotoxins Rabson-Mendenhall syndrome
such as hydrogen cyanide from spoiled tapioca or cassava root. (partial)
How these environmental insults lead to type 1 diabetes is Type A (mild)
Defects in other genes involved in insulin
unknown; they may directly damage β cells in some cases, or may
signaling
act as initiators or accelerators of the autoimmune attack on the Insulin receptor autoantibodies (Type B)
β cells. In some cases, molecular mimicry, wherein the immune
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Ataxia telangiectasia syndrome

system mistakenly targets β cell proteins that share homologies Secondary to other Cushing syndrome
with certain viral or other foreign peptides may play a role.
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endocrine disorders Acromegaly

Epidemiological studies have demonstrated an association Pheochromocytoma
Glucagonoma
between breast-feeding in the first 6 months of life and protection Hyperthyroidism
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from type 1 diabetes. While it has been suggested that proteins in Insulinoma
cow’s milk may be the culprits, the strongest evidence supports the Secondary to other Visceral obesity
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idea that human breast milk may reduce the risk of autoimmune disorders Stress (infection, surgery, etc)
disease. Uremia
Accumulating evidence shows that in the process of modern- Hyperglycemia (mild resistance seen in
type 1 diabetes)
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izing and improving public health, the risk of type 1 diabetes has Liver disease
increased, possibly due to the removal of some protective factors. Cytogenetic disorders (Down, Turner,
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Type 1 diabetes is almost unheard of in many third-world coun- Klinefelter)

Neuromuscular disorders (muscular dys-
tries, and has its highest incidence in countries with the best
trophies, ataxias, muscle inactivity)
public health systems, such as the Scandinavian countries. In addi- Congenital lipodystrophies/lipoatrophy
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tion, the incidence of the disease has been steadily increasing over Acquired lipodystrophy
the past century in western and westernizing countries and is Secondary to normal Puberty
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especially high among the more affluent. This has led to the sug- physiologic states Pregnancy
gestion that a dirty environment, one with more infections (espe- Starvation
o
cially more parasitic diseases) and more antigen exposure, may Secondary to Glucocorticoids
reduce the risk of type 1 disease. medications Atypical antipsychotic drugs
Antiretroviral protease inhibitors
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Nicotinic acid
Thiazide diuretics
TYPE 2 DIABETES
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Oral contraceptive
Progesterone
Type 2 diabetes mellitus—previously called non-insulin- β blockers
dependent diabetes or adult-onset diabetes mellitus—results from
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relative insulin deficiency, in contrast to the absolute insulin defi-

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ciency of patients with type 1 diabetes. Type 2 diabetes is a hetero-

geneous disorder and probably represents a large number of Most patients with type 2 diabetes, irrespective of weight, have
different primary genetic and environmental insults leading to some degree of tissue insensitivity to insulin attributable to several
lic
relative insulin deficiency—a mismatch between insulin produc- interrelated factors (Table 17–7). These include putative (mostly
tion and insulin requirements. Clinically, patients with type 2 as yet undefined) genetic factors, which are aggravated in time by
diabetes can range from those with severe insulin resistance and further enhancers of insulin resistance such as aging, a sedentary
at
minimal insulin secretory defects to those with a primary defect in lifestyle, and abdominal visceral obesity. Not all patients with
insulin secretion. obesity and insulin resistance develop hyperglycemia, however. An
e
Type 2 diabetes accounts for 80% to 90% of cases of diabetes underlying defect in the ability of the β cells to compensate for the
in the United States. These patients commonly present as adults increased demand determines which patients will develop diabetes
with some degree of obesity, although increasing rates of obesity in the setting of insulin resistance. Furthermore, both the tissue
are leading to earlier onset of the disease in adolescents and chil- resistance to insulin and the impaired β cell response to glucose
dren. At onset, most patients with type 2 diabetes do not require appear to be further aggravated by sustained hyperglycemia, which
insulin to survive, but over time their insulin secretory capacity may impede both insulin signaling and β cell function. Treatment
tends to deteriorate, and many eventually need insulin treatment that reduces the blood glucose levels toward normal reduces this
to achieve optimal glucose control. Ketosis seldom occurs sponta- acquired defect in insulin resistance and may also improve glu-
neously, and if present, it is a consequence of severe stress from cose-induced insulin release to some degree, although the long-
trauma or infection. term decline in β cell function continues.

Type 2 diabetes frequently goes undiagnosed for many years enhance (adiponectin) insulin signaling locally or in distal target
because the hyperglycemia may develop quite gradually and with- tissues (see Chapter 20). Levels of fat storage in adipocytes, along
out initial symptoms. Despite this mild presentation, these with insulin signaling itself, regulate the production and secretion
patients develop microvascular, and, especially, macrovascular of many of the adipokines. Some of these mediators of insulin
complications. Furthermore, as noted earlier, patients with type 2 resistance may reduce insulin signaling by blocking access of insu-
diabetes suffer from a progressive decline in β cell capacity, leading lin to target tissues through reduced transendothelial transit.
to worsening hyperglycemia over time. However, most evidence suggests that the secreted adipokines
influence insulin signaling in distant tissues through effects on
A. Obesity in type 2 diabetes The majority of people with postreceptor intracellular signaling pathways. Potential intracel-
type 2 diabetes have excess adiposity, although the prevalence of lular effectors include protein tyrosine phosphatases that dephos-
obesity in association with type 2 diabetes varies among different phorylate the receptor and pathway components, inhibitors such
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racial groups. Sixty to eighty percent of North Americans, Europe- as the SOCS proteins that block receptor–IRS interactions, and
ans, or Africans with type 2 diabetes and close to 100% of indi- serine/threonine kinases that inhibit the receptor and substrates
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viduals with type 2 disease among Pima Indians or Pacific Islanders through serine phosphorylation.
from Nauru or Samoa have obesity as defined by body mass index
(BMI, see Chapter 20), while as few as 30% of Chinese and Japa-
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Free fatty acids and ectopic lipid storage The release of

nese patients with type 2 diabetes are obese. However, many of fatty acids by the engorged adipocytes (especially visceral adipo-
those individuals with type 2 diabetes who do not meet BMI crite-
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cytes, from which fatty acids are more readily mobilized) may play
ria for obesity have a predominantly abdominal distribution of fat, a role in the development of insulin resistance as well. Oxidation
producing an abnormally high waist to hip ratio. Increases in vis- of fatty acids by muscle and other tissues could inhibit glycolysis
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ceral adiposity correlate with increased insulin resistance. and reduce insulin-stimulated glucose removal (the Randle
hypothesis, named after its original proponent). Increased fat stor-
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B. Insulin resistance in type 2 diabetes Insulin resistance age in adipocytes and release of fatty acids may also eventually
can be broadly defined as a decrease in tissue responsiveness to cause a shift in lipid storage, increasing lipid uptake and storage in
insulin. Clinically it can be assessed directly by measuring the abil- nonadipose tissues such as muscle, liver, and β cells. Ectopic lipid
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ity of a fixed dose of insulin to promote total body glucose dis- storage in these tissues may lead to a decrease in their insulin sen-
posal. It can be assessed indirectly by measuring fasting insulin sitivity. In addition, free fatty acids may function directly in a
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levels. An increase in insulin levels with normal plasma glucose signaling role both locally within the adipose tissue and
indicates insulin resistance. systemically.
o
As adiposity increases, especially abdominal visceral fat depos-

its, total body insulin sensitivity decreases. Since adipose tissue
Inflammation In addition to adipocytes, adipose tissue con-
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only removes a small fraction of plasma glucose, clearly the

tains a variety of other cell types including inflammatory/immune
increased adipose fat stores impact total body insulin sensitivity
cells, such as macrophages and lymphocytes. Recent evidence
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through effects on other tissues, especially muscle and liver, caus-

implicates these cells in obesity-induced insulin resistance. As
ing them to decrease insulin-stimulated glucose disposal. The
adipocyte lipid stores rise, the increased release of free fatty acids
exact means by which fat storage in adipocytes affects the insulin
and proinflammatory adipokines recruits macrophages to the
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sensitivity of other cells remains uncertain, but experimental evi-

adipose tissue and activates them. The activated macrophages then
dence suggests several possible mechanisms.
release a variety of molecules (TNF-α, IL-6, nitric oxide, and oth-
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Abnormalities of insulin receptors—in concentration, affinity,

ers) that decrease the insulin sensitivity of the adipocytes and
or both—affect insulin action. Target tissues downregulate the
further increase their release of proinflammatory fatty acids and
number of insulin receptors on the cell surface in response to
peptides, creating a positive feedback loop that maintains a
lic
chronically elevated circulating insulin levels, probably by

chronic state of local inflammation and insulin resistance. Release
increased intracellular degradation. When insulin levels are low,
of these adipokines and proinflammatory cytokines, along with
on the other hand, receptor binding is upregulated. Conditions
at
the increased release of free fatty acids and the development of

associated with high insulin levels and lowered insulin binding to
ectopic lipid accumulation, promotes the development of inflam-
the receptor include obesity, high intake of carbohydrates, and
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mation and insulin resistance in the other key insulin-target tis-

chronic exogenous overinsulinization. Conditions associated with
sues, such as muscle and liver. Similar mechanisms could also lead
low insulin levels and increased insulin binding include exercise
to inflammation in the islets and contribute to β cell failure.
and fasting. The insulin receptor itself is probably not the major
determinant of insulin sensitivity under most circumstances, how- PPARγ activity in the adipose tissue generally has beneficial
ever. Clinically relevant insulin resistance most commonly results effects on systemic insulin signaling through several mechanisms:
from defects in postreceptor intracellular signaling pathways. (1) Promotion of adipose lipid storage, which thereby decreases
ectopic lipid storage in nonadipose tissues; (2) Inhibition of the
Adipokines Adipose tissue can affect the insulin sensitivity of production of adipokines and proinflammatory cytokines, which
other tissues through the secretion of signaling molecules, adipo- promote insulin resistance, by adipocytes; (3) Promotion of the
kines, that inhibit (TNF-α, IL-6, leptin, resistin, and others) or alternative activation of macrophages to the anti-inflammatory

M2 state, rather than the proinflammatory M1 state; (4) Inhibi- response of their β cells to insulin resistance. Functionally, this
tion of the release of proinflammatory and proresistance cytokines defect is revealed by a reduction in first phase insulin secretion and
by macrophages. Although it is expressed at much lower levels in the maximal insulin secretion stimulated by glucose.
muscle than in adipose tissue, PPARγ in myocytes might also have While increased insulin secretion per β cell may contribute to
a direct role in controlling muscle insulin sensitivity; however, the compensatory response to insulin resistance, increases in the
these findings remain controversial. number of β cells play a role as well. In the setting of obesity,
hyperplasia of pancreatic β cells is often present and probably
Tissue heterogeneity in insulin resistance Finally, it must accounts for the normal or exaggerated insulin responses to glu-
be kept in mind that not all tissues necessarily develop insulin cose and other stimuli seen in obese individuals without type 2
resistance in parallel, and in many cases insulin resistance may be diabetes. Assessment of total β cell mass at autopsy has revealed
limited to specific tissues. The combination of local and systemic
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that β cell mass increases in obesity, but the individuals with type
contributors to obesity-induced insulin resistance may explain the 2 diabetes have decreased β cell mass when compared to nondia-
different levels of insulin resistance in different tissues of the same
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betic individuals with the same BMI.

patient. Even in the same cell, insulin resistance may impact dif- Several possible defects could contribute to the failure of β cell
ferent arms of the insulin-signaling pathway discordantly. As mass compensation in people with type 2 diabetes. Underlying
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insulin levels rise in response to insulin resistance, heterogene- genetic differences in the pathways that drive β cell expansion
ity in insulin sensitivity could explain unique syndromes associ- appear to limit compensation in individuals with high genetic risk
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ated with insulin resistance like hepatic steatosis and polycystic of diabetes. In susceptible individuals with obesity, ectopic fat
ovary syndrome. deposition in the islets, local obesity-induced inflammation in the
islets, and local and circulating adipokines and inflammatory
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Other causes of insulin resistance Visceral obesity is not cytokines may accelerate β cell loss. As β cell failure progresses,
the only cause of insulin resistance, although it is by far the most levels of glucose and free fatty acids start to rise, which in turn can
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common cause in most populations. Other causes of insulin cause further β cell toxicity. Increased demand on a decreased β cell
resistance include a variety of genetic and acquired defects that mass may cause further damage through ER stress and the
impact the insulin receptors or postreceptor signaling pathways increased formation of toxic IAPP oligomers. Then, once diabetes
y
(see Table 17–7). is established, all of these mechanisms may further contribute to
the progressive decline in β cell function that characterizes type 2
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Clinical consequences of insulin resistance In addition to diabetes.

the impact on glucose metabolism, severe insulin resistance and
o
the resulting elevation in circulating insulin levels can cause other D. Metabolic syndrome Patients with visceral obesity and
clinical consequences including acanthosis nigricans, pseudoacro- insulin resistance often present with a cluster of abnormalities com-
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megaly, and hyperandrogenism. Acanthosis nigricans appears to monly termed the metabolic syndrome. Hyperglycemia in these
be a consequence of very high circulating insulin levels that cross patients is frequently associated with hyperinsulinemia, dyslipid-
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over to bind to IGF receptors on epidermal and melanin-containing emia, and hypertension, which together lead to coronary artery
cutaneous cells. This leads to local skin hyperplasia with papillo- disease and stroke. It has been suggested that this aggregation
matosis, hyperkeratosis, and hyperpigmentation. The dark, vel- results from a genetic defect producing insulin resistance, particu-
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vety patches of skin most commonly appear on the back of the larly when obesity aggravates the degree of insulin resistance. In
neck, axillae, and anticubital fossae. In extreme and prolonged this model, impaired action of insulin predisposes to hyperglyce-
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cases of insulin resistance, the secondary increase in signaling mia, which in turn induces hyperinsulinemia. If this hyperinsu-
through the IGF-1 receptor, or possibly residual signaling through linemia is of insufficient magnitude to correct the hyperglycemia,
the mitogenic arm of the insulin signaling pathway, can cause type 2 diabetes is manifested. The excessive insulin level could also
lic
pseudoacromegaly, a syndrome with all of the bone and soft tissue increase sodium retention by renal tubules, thereby contributing to
changes of acromegaly (see Chapter 4), but no elevation in growth or causing hypertension. Increased VLDL production in the liver,
at
hormone or IGF-1. A similar action of extremely high insulin leading to hypertriglyceridemia (and consequently a decreased
levels on ovarian hilar cells has been implicated in women with high-density lipoprotein [HDL] cholesterol level), has also been
insulin resistance who develop hyperandrogenism and hirsutism
e
attributed to hyperinsulinism. Moreover, it has been proposed that

associated with menstrual irregularities, enlarged cystic ovaries and high insulin levels can stimulate endothelial and vascular smooth
infertility (polycystic ovary syndrome). muscle cell proliferation—by virtue of the hormone’s action on
growth factor receptors—to promote atherosclerosis.
C. a Cell defects in type 2 diabetes Although the majority Although there is full agreement on an association of these
of people with type 2 diabetes have insulin resistance, most people disorders, the mechanism of their interrelationship remains specu-
with insulin resistance do not have diabetes because their β cells lative and open to experimental investigation. Controversy persists
compensate for the insulin resistance by producing and secreting about whether or not hypertension is caused by the hyperinsulin-
more insulin. Those individuals with insulin resistance who ism that results from insulin resistance. Moreover, patients with
develop type 2 diabetes have a defect in the compensatory hyperinsulinism due to an insulinoma are generally normotensive,

and there is no reduction of blood pressure after surgical removal and GWAS. To date candidate gene and GWAS approaches have
of the insulinoma restores normal insulin levels. identified 19 loci with common variants linked to type 2 diabe-
An alternative unifying hypothesis could be that visceral obe- tes. Although statistically significant and validated in additional
sity directly induces the other components of this syndrome. populations, these loci independently make very small contribu-
Visceral obesity is an independent risk factor for all of the other tions to type 2 diabetes risk. The highest risk of these common
components of the metabolic syndrome. In addition to the meta- variants is found at a locus adjacent to the gene encoding
bolic effects of visceral obesity, the adipokines and inflammatory TCF7L2, a transcription factor involved in Wnt signaling and
cytokines generated from overloaded and inflamed adipose tissue implicated in β cell turnover. Inheritance of the high-risk
may contribute to the pathophysiology of the syndrome. Although TCF7L2 allele increases the probability of developing diabetes
the full details of the role of these molecules in causation of the by 1.5-fold.
metabolic syndrome remain under investigation, the adipocytes Among the genes identified so far, most are involved in β cell func-
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and associated macrophages clearly are not just innocent bystand- tion and turnover. When combined with the predominance of β
ers but play active roles in the development of systemic insulin cell genes implicated in mongenic forms of diabetes (see Table 17-5),
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resistance, hypertension, and hyperlipidemia. Furthermore, these results reinforce the critical role of the β cell in controlling
thrombi in atheromatous vessels may be more hazardous in blood glucose and its involvement in the pathophysiology of type
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patients with visceral obesity because of an associated increase in 2 diabetes. Hopefully, with the advent of high-throughput whole
plasminogen activator inhibitor-1 (PAI-1), a circulating factor genome sequencing technologies, the identification of rarer, but
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produced by omental and visceral adipocytes that inhibits clot higher risk, variants will further expand our understanding of the
lysis. This model emphasizes the importance of measures such as genetics of type 2 diabetes in the near future.
diet and exercise that reduce visceral adiposity in the management
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of patients with metabolic syndrome and obese type 2 diabetes. F. Environmental factors in type 2 diabetes Despite the
The main value of grouping these disorders as a syndrome, critical role of genetics in type 2 diabetes, environment contrib-
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regardless of its nomenclature, is to remind physicians that the utes as well, especially in determining the age of onset and severity
therapeutic goals in these patients must not only correct hypergly- of the disease. There is generally a low incidence of type 2 diabetes
cemia but also manage the elevated blood pressure and hyperlip- in underdeveloped countries, especially in rural areas. Western
y
idemia that result in considerable cardiovascular morbidity as well countries and westernizing countries suffer from a much higher
as cardiovascular deaths. In addition, it reminds physicians that incidence. Over the past half-century, the incidence of type 2
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when choosing antihypertensive agents or lipid-lowering drugs to diabetes has increased rapidly in almost all world populations but
manage one of the components of this syndrome, their possible especially in emerging third-world countries. This increase corre-
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untoward effects on other components of the syndrome should be lates with increasing rates of obesity in the same populations and
carefully considered. For example, physicians aware of this syn- reflects increased access to food with high caloric content and
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drome are less likely to prescribe antihypertensive drugs that raise decreased physical activity. This combination inevitably leads to
lipids (diuretics, beta blockers) or that raise blood glucose (diuret- increased adiposity, especially in the more readily mobilized fat
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ics). Likewise, they may refrain from prescribing drugs that correct stores surrounding the viscera in the abdomen.
hyperlipidemia, but increase insulin resistance with aggravation of One of the most dramatic recent changes in the epidemiology
hyperglycemia (nicotinic acid). of diabetes has been the growing incidence of type 2 diabetes in
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children. While rarely seen in children a generation ago, type 2

diabetes is now as common as type 1 diabetes in teenagers in the
E. Genetics of type 2 diabetes Type 2 diabetes has a strong
up
United States and is seen with increasing frequency, even in

genetic link. Depending on the population studied, monozygotic
younger children. Again, this increase is directly related to increas-
twins have lifetime concordance rates for type 2 diabetes exceed-
ing visceral adiposity.
ing 90%. In contrast, concordance rates for type 1 diabetes in
lic
monozygotic twins are 25% to 50%. Most individuals with type

2 diabetes have other family members with the disease, but the
MONOGENIC DIABETES
at
inheritance rarely fits Mendelian patterns, supporting the conclu-

sion that multiple genes with varying degrees of penetrance con-
Autosomal Dominant Genetic
e
tribute. Because of the heterogeneous nature of type 2 diabetes,

and its complex inheritance, efforts to identify the genes that Defects of Pancreatic a Cells
contribute to the disease have had very limited success in the vast MODY This subgroup of monogenic disorders is characterized by
majority of affected patients. There has been considerable success, the onset of diabetes in late childhood or before the age of 25 years
however, in identifying small subsets of patients with unique as a result of a partial defect in glucose-induced insulin release and
monogenic forms of the disease. When the etiologic defect has accounts for up to 5% of diabetes in North American and European
been defined, these patients have been reclassified within a group populations. A strong family history of early-onset diabetes occur-
designated “Monogenic Diabetes” (see Table 17–5). ring in one parent and in one-half of the parent’s offspring suggests
Efforts to identify the genes involved in polygenic type 2 autosomal dominant transmission. In contrast to most patients with
diabetes have focused on two approaches: candidate gene testing type 2 diabetes, these patients are generally nonobese and lack

associated insulin resistance. Instead they exhibit predominantly a glucose so that it requires higher plasma glucose levels to stimulate
defect in glucose-stimulated insulin secretion. However, because insulin secretion, resulting in fasting hyperglycemia and mild dia-
they are not ketosis-prone and may initially achieve good glycemic betes. Although some of these mutations can completely block the
control without insulin therapy, their disease has been called enzyme’s function, others interfere only slightly with its action. In
maturity-onset diabetes of the young (MODY). Several distinct contrast to all the other forms of MODY, most patients with one
types have been described with single-gene defects, and all have mutated GCK allele (heterozygotes) have a benign course with few
been shown to produce a defect in glucose-induced insulin release. or no chronic complications and respond well to diet therapy or
MODY 2 results from an abnormal glucokinase enzyme. Many of oral antidiabetic drugs without the need for insulin treatment. On
the other forms of MODY are due to mutations of nuclear tran- the other hand, rare individuals who inherit two mutated GCK
scription factors that control β cell function and formation by regu- alleles have permanent neonatal diabetes (discussed later), a non-
lating the expression of genes in β cells or their developmental immune form of absolute insulin deficiency that presents at birth.
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precursors (Figure 17–8 and Table 17–11). In contrast to the mutations that reduce glucokinase enzyme
MODY 1 includes multiple members of a large pedigree activity and cause MODY 2, rare mutations in GCK that increase
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known as the R-W family, descendants of a German couple who the enzymatic activity of glucokinase can cause increased insulin
immigrated to Michigan in 1861. They were studied prospectively secretion and hypoglycemia (see Chapter 18), demonstrating the
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since 1958, and in 1996 the genetic defect was shown to be a key role of this enzyme in determining the sensitivity of the β cell
nonsense mutation of a nuclear transcription factor found in liver to glucose.
as well as in pancreatic β cells. This gene has been termed hepato-
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MODY 3 is caused by mutations of hepatocyte nuclear factor 1α

cyte nuclear factor 4α (HNF4α) and is found on chromosome 20. (HNF1α), whose gene is located on chromosome 12. This is the
Mutations of this gene are among the rarest of the MODY groups, most common form of MODY in European populations, with
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with few reported in families outside the Michigan pedigree. many different mutations having been reported. Like HNF4α, the
These patients display a progressive decline in β cell function and HNF1α transcription factor is expressed in pancreatic β cells as
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eventually develop chronic complications of diabetes including well as in liver. Also similar to HNF4α, mutations in HNF1α
microangiopathy at a rate approaching that of people with type 1 cause a progressive form of diabetes with declining β cell function
diabetes. They often fare better with insulin therapy. that often leads to dependence on insulin therapy and high rates
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MODY 2 was first described in French families but has now of microvascular complications. Patients carrying HNF1α muta-
been found in racial groups from most parts of the world. Multi- tions often have reduced circulating levels of C-reactive protein.
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ple different mutations of the glucokinase gene (GCK) on chromo- Of note, early in the course of the disease, these patients may
some 7 have been identified and characterized. In pancreatic β cells, display an exaggerated response to sulfonylureas.
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glucokinase controls the rate-limiting step in glycolysis and Together, HNF1α and HNF4α, along with several other β
thereby determines the rate of ATP production from glucose and cell transcription factors including PDX1 and NEUROD1 (dis-
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the insulin secretory response to glucose (see Figure 17–5). cussed later), form an interacting network of transcription fac-
Reduced glucokinase activity resets the sensitivity of the β cell to tors (Figure 17–11). This transcriptional network regulates
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NeuroD1
Heterozygous Pax4 Pdx1
NeuroD1 Glis3
D
Homozygous Gata6
β-cell Mnx1 Pax6
Nkx2.2
Rfx6 Rfx6
up
Nkx2.2
Neurog
Neurog3
Hnf4a Gata4 α-cell Hnf1a
lic
Rfx6 Gata6 Hnf4a

Hnf1b
Glis3
at
Hnf1b
Mnx1 Duct cell
Ptf1a
Glis3
e
Nkx2.2 Gata4
Ptf1a
Acinar cell
Pancreatic
Endoderm
endoderm
progenitor
pancreas
Mature
Gut
cell
FIGURE 17–11 A simplified model is shown for the differentiation of pancreatic cell types during the development of the pancreas, start-
ing with the formation of the definitive endoderm. Transcription factors involved in this process and also implicated in human diabetes are
shown at their major expression time points, and are labeled in orange if heterozygous mutations cause diabetes and in red if only homozy-
gous mutations have been shown to cause diabetes.

genes involved in both the development of the β cell as well as TABLE 17–8 Autosomal dominant genetic defects of
mature β cell function, including glucose-sensing and insulin pancreatic a cell function.
secretion. Target genes include GCK, as well as genes implicated
in the formation, maturation and expansion of β cells. Impair- Syndrome Mutated Protein Gene Function
ment in β cell formation and regeneration may explain the pro- MODY 1 Hepatocyte nuclear HNF4A Transcription
gressive nature of the MODY transcription factor syndromes factor-4α factor
and reinforces the importance of β cell mass in preventing MODY 2 Glucokinase GCK Glucose
hyperglycemia. sensor
MODY 4 results from mutation of a pancreatic nuclear tran- MODY 3 Hepatocyte nuclear HNF1A Transcription
scription factor known as pancreatic and duodenal homeobox-1 factor-1α factor
(PDX1), whose gene is on chromosome 13. It mediates insulin
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MODY 4 Pancreatic duodenal PDX1 Transcription

gene transcription and regulates expression of other β cell-specific homeobox-1 factor
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genes including GCK. When both alleles of this gene are nonfunc- MODY 5 Hepatocyte nuclear HNF1B Transcription
tioning, agenesis of the entire pancreas results; but in the presence factor-1β factor
of a heterozygous mutation of PDX1, a mild form of MODY has MODY 6 NeuroD1 NEUOROD1 Transcription
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been described in which affected individuals developed diabetes at factor

a later age (mean onset at 35 years) than occurs with the other MODY 7 Kruppel-like KLF11 Transcription
factor 11 factor
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forms of MODY, in whom onset generally occurs before the age

of 25 years. MODY 8 Carboxyl-ester lipase CEL Exocrine
enzyme
MODY 5 was initially reported in a Japanese family with a
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mutation of HNF1β, a hepatic nuclear transcription factor closely MODY 9 Paired homeobox 4 PAX4 Transcription
factor
related in structure and molecular function to HNF1α. The two
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HNF1 factors, however, are expressed by different cells. HNF1β is MODY 11 Tyrosine-protein BLK Intracellular
kinase Blk signaling
expressed early in the development of the liver, pancreas, kidneys,
and genitourinary system, and is not found in mature β cells. MODY 14 Adaptor Protein APPL1 Intracellular
y
APPL1 signaling
Mutations in this gene cause a moderately severe form of
GATA4 GATA-binding GATA4 Transcription
MODY with progression to insulin treatment and severe diabetic
protein 4 factor
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complications in those affected. Consistent with its expression

GATA6 GATA-binding GATA6 Transcription
pattern early in development, HNF1β mutations also frequently protein 6 factor
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cause reduction in the overall size of the pancreas, decreased insu-

Mutant Preproinsulin INS Hormone
lin production, and congenital defects in the kidney and urogeni- insulin or
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tal tract. Patients may also suffer from varying degrees of Proinsulin
cholestatic jaundice, hyperuricemia, nephropathy, and hypomag- KATP Inward-rectifying K+ KCNJ11 Ion channel
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nesemia secondary to renal magnesium wasting. mutations channel 6.2

MODY 6, a milder form of MODY similar to MODY 4, Sulfonylurea ABBC8 Ion channel
results from mutations in the gene encoding the islet transcription receptor 1
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factor NeuroD1. Like PDX1, NeuroD1 plays an important role in

the expression of insulin and other β cell genes, and in the forma-
up
tion and maintenance of β cells.

ISL1, PAX6, and PAX4 (later onset diabetes). Heterozygous
Other MODY genes The six MODY genes listed earlier explain GATA4 and GATA6 mutations can also be associated with pan-
the majority of cases of MODY in patients of European ancestry,
lic
creatic agenesis and congenital cardiac defects. The association of

but less than half of those in non-European populations. Several diabetes with heterozygous mutations in so many β cell genes
rare variants in other genes have been implicated in autosomal highlights the critical importance of optimal β cell function in
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dominant diabetes in a few families (see Table 17–8); however, a metabolic regulation. Even modest defects in glucose-induced
consensus has not yet been reached that these families fit the cri- insulin secretion can result in hyperglycemia.
e
teria for MODY and that the reported variants cause the disorder.
The causative genes in most non-Europeans with MODY remain Insulin mutations Sequencing of the insulin gene more than
unknown. 30 years ago led to the first descriptions of heterozygous mutations
The identification of mutations in multiple genes encoding in the coding sequence of the insulin gene that produce abnormal
pancreatic transcription factors in patients with MODY has led to circulating forms of insulin. Most of these initial cases presented
the screening of other genes encoding pancreatic transcription fac- with high circulating levels of insulin, but normal insulin sensitiv-
tors in patients with diabetes. Heterozygous mutations in genes ity and normal glucose levels. Because the abnormal insulins in
encoding several transcription factors have been identified in these cases bind to receptors poorly, they have very low biologic
patients with earlier or later onset diabetes than in MODY activity and are cleared at a slower rate, leading to accumulation
patients, including GATA6 and GATA4 (neonatal diabetes) and in the blood at higher levels than normal insulin and a subnormal

molar ratio of C peptide to immunoreactive insulin. They typi- prevent glucose-induced depolarization and insulin secretion.
cally are not associated with hyperglycemia. Children heterozygous for these mutations present with early-
However, a mutation in the insulin B chain in one family was onset diabetes, commonly as neonates, and may have associated
associated with decreased circulating levels of both the mutant and neurologic deficits implying a role for these channels in the central
normal insulins, and diabetes. Subsequent extensive sequencing of nervous system. Depending on the exact mutation, some of these
the INS gene has identified many other mutant insulins that pro- children can still respond to treatment with sulfonylureas, which
duce a similar heterozygous form of diabetes. Modeling of these may also ameliorate the neurologic symptoms.
dominant insulin mutations in mice demonstrates that they lead
to the accumulation of aberrantly folded proteins in the endoplas- Other Genetic Defects of Pancreatic a Cells
mic reticulum, activation of the unfolded protein response in the Autosomal recessive genetic defects Although less com-
ER, and β cell apoptosis. Patients with diabetes secondary to INS
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mon than the autosomal dominant β cell disorders, mutations in

gene mutations usually present at a younger age than most several genes causing autosomal recessive syndromes with defects
patients with MODY, often developing the disease as neonates
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in β cell function have been identified in patients with diabetes

(see Neonatal Diabetes later). Because of the profound β cell loss, (Table 17–9). Due to the severity of the β cell defect, many of
these patients follow a disease course similar to type 1 diabetes these present with neonatal diabetes. This group of disorders
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with absolute insulin deficiency and ketosis, and they require includes homozygous mutations in the MODY genes GCK,
insulin therapy. PDX1, and NEUROD1. Homozygous mutations in GCK cause a
This syndrome highlights the sensitivity of the β cells to ER
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much more severe syndrome than the mild glucose-sensing defect

stress, which may explain why β cells often fail when presented with seen in MODY 2. Patients with homozygous GCK mutations
the increased insulin demands associated with insulin resistance, the present at birth with severe hyperglycemia and require insulin
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toxicity of IAPP oligomers, or mutations in genes involved in the

therapy.
unfolded protein response pathway (discussed later).
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In patients with mutations in both alleles of PDX1, the pan-

Mutations in the subunits of the ATP-sensitive potassium creas fails to form, and they have pancreatic exocrine deficiency as
channel β cells sense rising blood glucose concentrations by well as diabetes. Homozygous mutations in several other pancre-
y
increasing the production of ATP from glucose. The rising intra- atic transcription factor genes have been described as well, includ-
cellular ATP levels cause the closure of ATP-sensitive potassium ing PTF1A, NEUROG3, RFX6, NKX2-2, MNX1, and GLIS3.
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channels on the cell surface, which depolarizes the cell and sets off Like PDX1, homozygous mutation of PTF1A causes diabetes and
a cascade of events that leads to the secretion of insulin (see Figure pancreatic agenesis, but it causes cerebellar atrophy as well. The
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17–5). Rare dominant activating mutations in either of the two transcription factor Neurog3 drives the formation of the endo-
units of the channel, SUR1 and Kir6.2 (gene names ABCC8 and crine cells in both the pancreas and gut. In addition to diabetes
KCNJ11, respectively), can cause the channels to remain open and onset prior to puberty, infants born with homozygous NEUROG3
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TABLE 17–9 Autosomal recessive genetic defects of pancreatic a cell function.

Function Protein Gene Associated Defects
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Glucose sensing Glucokinase GCK

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Transcription Pancreatic duodenal homeodomain protein 1 PDX1 Pancreatic agenesis

factors Pancreatic transcription factor 1a PTF1A Pancreatic and cerebellar agenesis
Neurogenenin3 NEUROG3 Absence of gut endocrine cells, malabsorption
Regulatory factor X-box 6 RFX6 Mitchell-Riley syndrome: absence of gut endocrine and islet
lic
α, β, and δ cells, pancreatic and gall bladder hypoplasia,

intestinal atresia, malabsorption
GLI Similar-3 GLIS3 Hypothyroidism, cholestasis, polycystic kidneys, hypoplastic
at
pancreas
NK homeodomain protein 2-2 NKX2-2 Severe developmental delay, hypotonia, cortical blindness,
impaired visual tracking, and hearing impairment
e
Motor neuron and pancreas homeodomain MNX1 Severe developmental delay and neurological deficits, sacral
protein 1 agenesis
Unfolded pro- Eukaryotic translation initiation EIF2AK3 Wolcott-Rallison syndrome: epiphyseal dysplasia and growth
tein response factor 2-α kinase 3/PKR-like ER retardation; variable hepatic, renal, cardiac, and pancreatic
kinase (PERK) exocrine defects
Immediate early response 3 interacting protein 1 IER3IP1 MEDS syndrome: microcephaly, epilepsy
Wolfram syndrome protein 1 (WFS1) WFS1 Wolfram syndrome: diabetes insipidus, diabetes mellitus,
optic atrophy, and deafness (DIDMOAD)
Thiamine Solute carrier family 19 (thiamine transporter), SLC19A2 Thiamine-responsive megaloblastic anemia: anemia,
transport member 2 deafness

mutations have severe malabsorption associated with a lack of gut transport thiamine through lower affinity transporters, and both
endocrine cells from birth. the anemia and the diabetes respond to pharmacologic treatment
Homozygous mutations in RFX6, which encodes a transcrip- with thiamine. However, all patients eventually require insulin
tion factor that functions downstream of NEUROG3 and replacement despite thiamine therapy. It remains unclear how
upstream of PDX1 in β cell development, cause Mitchell–Riley partial defects in cellular and mitochondrial thiamine transport
syndrome in which neonates present with diabetes in association cause β cell failure.
with complete absence of all islet cell types except PP cells, hypo-
plasia of the pancreas and gall bladder, intestinal atresia, and severe Mitochondrial DNA mutations Because sperm do not con-
malabsorption. tain mitochondria, only the mother transmits mitochondrial
The zinc finger transcription factor GLIS3 is expressed broadly genes to her offspring. Diabetes due to a mutation of mitochon-
in many tissues and plays a role in the transcription of the insulin drial DNA that impairs the transfer of leucine into mitochondrial
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gene. Homozygous mutations in GLIS3 cause congenital hypo- proteins has now been described in a large number of families, and
thyroidism in addition to neonatal diabetes. results from impaired β cell function. The incidence of this disor-
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In the autosomal recessive Wolcott–Rallison syndrome, der is as high as 1% to 3% in patients with diabetes in Japan and
affected children present with neonatal diabetes, epiphyseal dys- Korea, but lower in European populations. Most patients have a
mild form of maternally transmitted diabetes with insulin defi-
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plasia, and growth retardation together with a variety of progres-

sive hepatic, renal, cardiac, and pancreatic exocrine defects and ciency that responds to oral hypoglycemic agents; however, some
patients have a more severe clinical picture similar to type 1a dia-
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developmental delay. The causative gene, EIF2AK3, encodes a

kinase (PKR-like ER kinase [PERK]) activated by the presence of betes. As many as 63% of patients with this subtype of diabetes
unfolded proteins in the ER. PERK controls one of the three have hearing loss and a smaller proportion (15%) have a syndrome
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parallel arms of the unfolded protein response; inositol-requiring of myopathy, encephalopathy, lactic acidosis, and stroke-like
enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) episodes.
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activate the other two arms. Together these three molecules acti-
vate signaling pathways that protect the cell from ER stress but
lead to apoptosis when these protective mechanisms fail. Mice Ketosis-Prone Diabetes
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lacking PERK have an inadequate response to ER stress, which First described in young adult African American males from the
leads to accelerated β cell apoptosis. With the high load of insulin Flatbush neighborhood in New York City, but since described in
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production in the ER, β cells are uniquely sensitive to ER stress, a number of populations of both African and non-African ances-
and this sensitivity probably underlies the damage caused by try, these patients typically present with diabetic ketoacidosis and
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mutant insulins, IAPP oligomers, and Wolfram syndrome as well. absolute insulin deficiency, followed by extended clinical remis-
Wolfram syndrome is an autosomal recessive neurodegenera- sion off insulin. When tested during remission, however, maximal
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tive disorder first evident in childhood. Patients present with dia- insulin secretory capacity remains markedly reduced, and these
betes insipidus, diabetes mellitus, optic atrophy, and patients follow a relapsing course of DKA and hyperglycemia with
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deafness—hence the acronym DIDMOAD. Diabetes mellitus eventual permanent insulin-deficient diabetes. These patients do
usually develops in the first decade together with the optic atro- not have islet cell autoantibodies or increased frequencies of HLA
phy, followed by central diabetes insipidus and sensorineural deaf- haplotypes associated with risk of autoimmune type 1a diabetes.
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ness during the second decade in 60% to 75% of patients. Although there is often a family history of similar diabetes, the
Ureterohydronephrosis, neurogenic bladder, cerebellar ataxia, inheritance is not clearly Mendelian. Although KPD patients have
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peripheral neuropathy, and psychiatric illness develop later in been distinguished based on the history of relapsing β cell dys-
many patients. The diabetes mellitus is nonimmune and not function, it remains controversial as to whether KPD represents a
linked to specific HLA haplotypes, but on autopsy these patients clinical entity distinct from other forms of nonautoimmune type
lic
have selective loss of β cells in the pancreas. Genetic studies 1b diabetes.

mapped the causative mutations to a gene called WFS1, which In a study of KPD patients of West African ancestry, linkage
encodes a 100.3-kDa transmembrane protein localized to the was established with coding variants in the PAX4 gene. PAX4
at
endoplasmic reticulum membranes of all cells. WFS1 is expressed encodes for a transcription factor that functions downstream of
at particularly high levels in β cells. Studies in mice have shown NEUROG3 in the formation of β cells. Fourteen to twenty-one
e
that the WFS1 protein forms part of the unfolded protein percent of individuals of West African ancestry carry a coding vari-
response downstream of PERK and IRE1 and helps protect the ant that substitutes tryptophan for arginine at position 133 in
β cells from ER stress and apoptosis, especially during periods of PAX4 and reduces its ability to repress transcription of target
high insulin demand. genes. Interestingly, the R133W variant is unique to people of
Children with thiamine-responsive megaloblastic anemia West African ancestry. The R133W allele is approximately twice
syndrome carry mutations in the high-affinity thiamine trans- as frequent in individuals with KPD, and all individuals homozy-
porter SLC19A2 found on cell and mitochondrial membranes. gous for R133W have KPD. An additional PAX4 coding variant
They develop megaloblastic anemia, diabetes, and sensorineuronal with reduced ability to bind to DNA was identified in one patient
deafness. The diabetes usually presents in the first decade of life. with KPD. Different coding variants in PAX4 have also been iden-
In the absence of SLC19A2, cells and mitochondria can still tified in Thai families with MODY (MODY 9) and in Japanese

patients (both heterozygous and homozygous) with early onset been helpful in human cases of generalized lipodystrophy, demon-
insulin-deficient diabetes similar to KPD. Taken together, these strating the importance of the adipocyte in regulating insulin
data suggest that coding variants in the PAX4 gene predispose to function. Also, the loss of adipose storage depots in lipoatrophy
insulin-deficient diabetes, but the clinical phenotype may depend leads to very high levels of circulating triglyceride-rich lipoprotein
on the exact nature of the variant and interactions with other particles and increased deposition of fat in nonadipose tissues such
genes and environmental factors. as liver and muscle, which may contribute to dysfunction and
insulin resistance in these tissues. The increase in ectopic fat depo-
sition leads to profound hepatic steatosis in affected patients and
Genetic Defects of Insulin Action can progress to cirrhosis and liver failure.
These are rare and unusual causes of diabetes that result from The congenital syndromes can be divided into generalized and
mutations of the insulin receptor or from other genetically deter- partial lipodystrophies with or without dystrophic features in
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mined postreceptor abnormalities of insulin action. Metabolic other tissues. The generalized syndromes are often identified in
abnormalities associated with these disorders may range from neonates, have severe insulin resistance at diagnosis and rapidly
ev
hyperinsulinemia and modest hyperglycemia to severe diabetes. develop hyperglycemia, acanthosis nigricans, hyperandrogenism,
Many individuals have acanthosis nigricans, polycystic ovaries and pseudoacromegaly. Recessive mutations causing generalized
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with hyperandrogenism, and, in exceptional cases, pseudoacro- congenital lipodystrophy have been identified in three genes
megaly (discussed earlier). encoding proteins involved in the formation of lipid droplets
Familial forms of insulin resistance associated with acanthosis
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(seipin and caveolin-1) and triglyceride (1-acylglycerol-3-phosphate-

nigricans have been termed type A insulin resistance, and are often O-acyltransferase 2 [AGPAT2]).
associated with heterozygous mutations in the insulin receptor or Two syndromes of familial partial lipodystrophy without associ-
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homozygous mutations that retain some insulin-signaling capac- ated dysmorphic defects have been described in which the lipoatro-
ity. Because of the capacity of the β cell to compensate for insulin phy usually first appears late in childhood, but may be proceeded by
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resistance, these patients often do not present with hyperglycemia, evidence of insulin resistance. The type 1 syndrome consists of
but have severely elevated levels of circulating insulin. atrophy of limb, gluteal and subcutaneous abdominal fat with spar-
If both copies of the insulin receptor gene carry mutations that ing or increases of the abdominal visceral, upper trunk, head, and
y
nearly or completely abrogate signaling, the affected children pres- neck fat. In the type 2 syndrome, truncal and visceral fat are also
ent at birth with a syndrome known as Leprechaunism (or Dono- affected and only vulval and head and neck depots are spared.
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hue syndrome) that includes growth retardation, multiple To date no genetic causes of the type 1 syndrome have been
developmental defects, lipoatrophy, severely elevated insulin levels, identified. In the type 2 syndrome, dominant mutations have
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and hyperglycemia that does not respond to insulin therapy. These been found in LMNA, the gene encoding the nuclear intermediate
patients generally do not survive beyond a few weeks. Patients with filament lamin A/C. In addition, one individual with the type 2
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Rabson–Mendenhall syndrome also have homozygous or com- syndrome has been identified with a homozygous nonsense muta-
pound heterozygous mutations in the insulin receptor, but with tion in the gene encoding the lipid droplet protein CIDEC, and
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some small amount of residual signaling that results in a slightly less one individual was identified with a homozygous truncation of
severe syndrome associated with abnormalities in the nails, teeth, the gene encoding lipase maturation factor 1, a protein required
and pineal gland. They may survive into adolescence. for the maturation of both lipoprotein lipase and hepatic lipase.
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Familial forms of type A insulin resistance without mutations Consistent with its known role in adipocytes differentiation,
in the insulin receptor have been described, and some of these may dominant mutations in the gene encoding PPARγ have also been
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result from mutations in downstream components of the insulin- described in patients with familial partial lipodystrophy and insu-
signaling cascade, although to date few such mutations have been lin resistance. These patients have a pattern of lipoatrophy similar
found in humans. Variants in IRS-1 have been identified in to the type 2 syndrome with LMNA mutations, but with less
lic
patients with diabetes, but also occur in people with normal insu- severe subcutaneous fat loss, and have been labeled type 3 familial
lin sensitivity. Rare coding mutations in the genes encoding the partial lipodystrophy. Less commonly, mutations in the PLIN1,
p85α subunit of PI3 kinase, in AKT2, and in PPARγ have been AKT2 and CIDEC genes have been associated with familial forms
at
associated with severe insulin resistance in a very small number of of partial lipodystrophy.
patients. The one patient with homozygous mutation of AKT2 Several syndromes of lipodystrophy associated with other dys-
e
also had mild atrophy of subcutaneous limb adipose tissue. morphic features have been described. Autosomal recessive muta-
Congenital and acquired forms of lipodystrophy can cause tions in ZMPSTE24, which encodes a metalloproteinase that
severe insulin resistance. Except in newborns with lipoatrophy cleaves prolamin A to produce mature lamin A, cause generalized
secondary to complete loss of insulin receptors (Leprechaunism), lipodystrophy associated with mandibuloacral dysplasia. In
alterations in the structure and function of the insulin receptor patients with partial lipodystrophy combined with mandibuloac-
cannot be demonstrated in patients with insulin-resistant lipodys- ral dysplasia, autosomal recessive mutations have been identified
trophic diabetes, suggesting that the cause of the insulin resistance in LMNA, but these mutations are distinct from those that cause
in these patients must reside in postreceptor pathways. Replace- familial partial lipodystrophy type 2. Remarkably, yet a different
ment of the adipokines leptin and adiponectin can reverse insulin set of mutations in LMNA cause the autosomal recessive syn-
resistance in mouse models of severe lipoatrophy, and leptin has drome Hutchinson–Gilford progeria, which includes severe early

onset generalized lipodystrophy. Additional distinct mutations in syndrome gene EIF2AK3. The IPEX syndrome (see Genetics of
LMNA cause several other congenital dysmorphic syndromes, Type 1 Diabetes, discussed earlier), caused by mutations in
including muscular dystrophies, familial dilated cardiomyopathy, FOXP3, can also present with accelerated autoimmune type 1
and Charcot-Marie-Tooth disease. diabetes in neonates. Finally, mutations that cause complete, or
Acquired forms of partial and generalized lipodystrophy with nearly complete, loss of insulin signaling (Leprechaunism) also
insulin resistance and diabetes can develop secondary to infec- present with PNDM.
tions, autoimmunity, paraneoplastic syndromes, collagen vascular Several other syndromes of neonatal diabetes of unknown eti-
disorders, drugs, or unknown causes. One common form is seen ology associated with a variety of other developmental defects have
in patients with HIV infection following treatment with protease been described. With the advent of rapid whole genome sequenc-
inhibitors. ing, the genetic defects that cause these syndromes, as well as later
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onset diabetes, may soon be identified, providing further insights

Neonatal Diabetes into the pathogenesis of diabetes and identifying potential thera-
ev
Neonatal diabetes, defined as diabetes diagnosed before 6 months peutic targets.

of age, is rare, occurring in fewer than 1 in 200,000 live births.
Children with neonatal diabetes often present with decreased Monogenic Autoimmune Syndromes
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birth weight (intrauterine growth restriction, IUGR) and decreased Several syndromes of altered immune function with multiple
fat stores in addition to hyperglycemia. Most commonly these endocrine gland involvement caused by single gene mutations
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children have reduced circulating insulin and C-peptide levels have been described. The APS1 and IPEX syndromes are described
caused by inherited β cells defects, although rare inherited defects in the section on the genetics of type 1 diabetes and in Chapter 2.
in insulin signaling can also present in neonates. In approximately
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Recently several additional monogenic autoimmune syndromes

half of cases, neonatal diabetes is transient: the diabetes goes into that include type 1 diabetes have been identified with autosomal
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remission (normoglycemia with no therapy) before 18 months of dominant (STAT1, STAT3, and SIRT1) or recessive (IL2RA,
age, although it usually returns at puberty. In the remainder of ITCH, and LRBA) inheritance.
cases, the diabetes is permanent.
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Transient neonatal diabetes (TNDM) Defects in imprinting

Other Genetic Syndromes Sometimes
underlie most cases of TNDM. The most common genetic defect Associated with Diabetes
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is paternal uniparental isodysomy (replacement of the maternal More than 50 distinct genetic syndromes involve an increased
copy of the region with the paternal copy) of an imprinted region
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incidence of diabetes mellitus. These include the chromosomal

at chromosome 6q24. In this region, the maternal copy of the abnormalities of Down syndrome, Klinefelter syndrome, and
chromosome is normally silenced by methylation. Simple duplica- Turner syndrome. In addition, a number of complex syndromes
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tion of the paternal copy of this region, or mutations in ZFP57, a associated with neuromuscular pathologies (Freidriech ataxia,
zinc-finger protein required globally for the methylation of Huntington chorea, porphyria, muscular dystrophies) or severe
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imprinted regions, can give the same TNDM phenotype. The obesity (Laurence–Moon–Biedl, Bardet–Biedl, and Prader–Willi
affected region of 6q24 contains two genes of uncertain function, syndromes) have been associated with diabetes.
but one of them, ZAC, has been identified as a tumor suppressor
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gene and may activate the expression of an inhibitor of cell prolif-

eration. An increase in hypomethylated copies of ZAC may lead to SECONDARY DIABETES
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the inhibition of β cell proliferation and inadequate β cell mass.

Some autosomal dominant activating mutations in KCNJ11
Diabetes due to Diseases of the
Exocrine Pancreas
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and ABCC8, the genes encoding the two subunits of the ATP-
sensitive potassium channels in β cells (see Figure 17–5) and listed Any process that diffusely damages or substantially displaces the
among autosomal dominant forms of heritable diabetes (discussed pancreas can cause diabetes, although individuals with a predispo-
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earlier) can cause TNDM. Autosomal dominant mutations in the sition to type 2 diabetes are probably more susceptible to develop-
MODY 5 gene, HNF1β, can also cause TNDM. ing diabetes with lesser degrees of pancreatic involvement. Because
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glucagon-secreting α cells are also damaged or removed by these

Permanent neonatal diabetes (PNDM) Autosomal domi- processes, less insulin is usually required for replacement—as com-
nant activating mutations in KCNJ11 and ABCC8 can also cause pared with most other forms of diabetes that leave α cells intact.
PNDM. Some of the autosomal dominant insulin mutations that Acquired causes include pancreatitis, trauma, infection, pan-
cause rapid β cell apoptosis will result in permanent diabetes in creatic carcinoma, and pancreatectomy. Fibrocalculous pancrea-
neonates. In addition, most of the syndromes caused by autosomal topathy, a form of acquired pancreatitis with extensive fibrosis and
recessive genetic defects in β cells (see Table 17–9) present in ductal calculi seen commonly in tropical regions, may result from
neonates. These include mutations in the MODY genes GCK, both dietary and genetic contributors, although the exact cause
PDX1, and NEUROD1, the transcription factor genes NKX2-2, remains obscure. Like chronic pancreatitis from a variety of causes,
MNX1, PTF1A, GLIS3, and RFX6, and the Wolcott–Rallison fibrocalculous involvement of the pancreas may be accompanied

by abdominal pain radiating to the back and associated with pan- secretion and hepatic glucose output. However, although β blockers
creatic calcifications on x-ray. When extensive enough, hemochro- and α2 agonists like clonidine, as well as calcium channel block-
matosis and cystic fibrosis can also displace β cells and reduce ers, inhibit glucose-induced insulin release from in vitro prepara-
insulin secretion. Autosomal dominant mutations in carboxyl- tions of pancreatic β cells, these drugs have minimal or modest
ester lipase (CEL), an exocrine enzyme, cause accelerated exocrine effects on blood glucose control at the levels used in standard
pancreatic damage and diabetes at a young age, and have been antihypertensive therapy in humans.
designated as MODY 8 (see Table 17–8). Finally it must be kept in mind that the most common toxin
causing diabetes is ethanol. Chronic alcoholic pancreatitis with
secondary loss of β cells accounts for approximately 1% of diabe-
Endocrinopathies
tes in the United States.
Excess production of certain hormones—GH (acromegaly), glu-
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cocorticoids (Cushing syndrome or disease), catecholamines

(pheochromocytoma), thyroid hormone (thyrotoxicosis), gluca-
Infections Causing Diabetes
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gon (glucagonoma), or pancreatic somatostatin (somatostatin- Certain viruses have been associated with direct pancreatic β cell
oma)—can produce relative insulin deficiency and diabetes by a destruction in animals. Diabetes is also known to develop fre-
number of mechanisms. In all but the last instance (somatostati- quently in humans who had congenital rubella, although most of
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noma), peripheral responsiveness to insulin is impaired. In addi- these patients have HLA and immune markers characteristic of
tion, excess of catecholamines or somatostatin decreases insulin type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus,
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release from β cells. Diabetes mainly occurs in individuals with adenovirus, and mumps have been implicated in inducing certain
underlying defects in insulin secretion, and hyperglycemia typi- cases of diabetes.
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cally resolves when the hormone excess is corrected.

Uncommon Forms of Immune-Mediated
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Drug- or Chemical-Induced Diabetes Diabetes

Many drugs are associated with carbohydrate intolerance or frank A severe form of insulin resistance has been reported in patients
who developed high titers of antibodies that bind to the insulin
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diabetes mellitus. Some act by interfering with insulin release from

the β cells (thiazides, phenytoin, cyclosporine), some by inducing receptor and block the action of insulin in its target tissues. As in
other states of extreme insulin resistance, these patients often have
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insulin resistance (glucocorticoids, oral contraceptive pills, niacin,

and antiviral protease inhibitors), and some by causing β cell acanthosis nigricans. In the past, this form of immune-mediated
diabetes was termed type B insulin resistance. Most commonly
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destruction (intravenous pentamidine). Atypical antipsychotic

medications can provoke substantial weight gain and insulin resis- these antibodies are of idiopathic origin, but they have also been
tance, but the high reported incidence of diabetic ketoacidosis in described in monoclonal gamopathies and multiple myeloma and
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patients on these drugs suggests that they may also impair β cell in patients with ataxia telangectasia syndrome.
function. Patients with POEMS, a syndrome of plasma cell dyscrasia
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The increasing therapeutic use of drugs that block inhibitory associated with polyneuropathy, organomegaly, endocrinopathy,
immune system pathways that keep immune responses in check monoclonal gammopathy, and skin changes, have an increased
has led to the development of new syndromes of autoimmunity incidence of diabetes as well as other endocrine disorders. The
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including autoimmune diabetes (essentially a secondary form of cause of the diabetes in these patients has not been established.
type 1 diabetes). Both α interferon used to treat Hepatitis C and
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immune checkpoint inhibitors such the monoclonal antibodies CLINICAL FEATURES OF

against PD-1 and CTLA-4 used to treat cancer have been associ-
DIABETES MELLITUS
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ated with development of a fulminant form of autoimmune dia-

betes similar to type 1 diabetes, as well as other endocrine and
The principal clinical features of the two major types of diabetes
non-endocrine autoimmune disorders.
mellitus are listed for comparison in Table 17–10.
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Adrenergic drugs impact glucose metabolism in complex and

often opposing ways because of differing effects on insulin secre-
Type 1 Diabetes
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tion, glucagon secretion, hepatic glucose output, peripheral insu-

lin sensitivity, and weight gain. In clinical practice, the first Patients with type 1 diabetes present with symptoms and signs
generation, nonselective β blockers such as propanolol tend to related to hyperglycemia and hyperketonemia. The severity of the
modestly increase glucose levels, at least in part due to increases in insulin deficiency and the acuteness with which the catabolic state
insulin resistance, but potentially by decreasing insulin secretion develops determine the intensity of the osmotic and ketotic excess.
as well. The second generation, selective β1 blockers also tend to
increase blood glucose, but the third generation drugs with com- A. Symptoms Increased urination is a consequence of osmotic
bined α and β blockade have minimal effects on blood glucose. In diuresis secondary to sustained hyperglycemia. This results in a
contrast, nonselective α agonist and α2 agonists tend to raise loss of glucose as well as free water and electrolytes in the urine.
blood glucose, probably due to their combined effects on insulin Nocturnal enuresis due to polyuria may signal the onset of

TABLE 17–10 Clinical features of diabetes at in a stuporous patient, with rapid deep breathing and the fruity
diagnosis. breath odor of acetone, suggests the diagnosis of diabetic
ketoacidosis.
Diabetes Diabetes
Postural hypotension indicates a depleted plasma volume;
Type 1 Type 2
hypotension in the recumbent position is a serious prognostic
Polyuria and thirst ++ + sign. Loss of subcutaneous fat and muscle wasting are features of
Weakness or fatigue ++ +
Polyphagia with weight loss ++ –
more slowly developing insulin deficiency. In occasional patients
Recurrent blurred vision + ++ with slow, insidious onset of insulin deficiency, subcutaneous fat
Vulvovaginitis or pruritus + ++ may be considerably depleted. An enlarged liver, eruptive xantho-
Peripheral neuropathy + ++ mas on the flexor surface of the limbs and on the buttocks, and
Nocturnal enuresis ++ –
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Often asymptomatic – ++ lipemia retinalis indicate that chronic insulin deficiency has
resulted in chylomicronemia, with elevated circulating triglycer-
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ides, usually to over 2000 mg/dL (Chapter 19).
diabetes in very young children. Thirst is a consequence of the Type 2 Diabetes

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hyperosmolar state, as is blurred vision, which often develops as

the lenses and retinas are exposed to hyperosmolar fluids. Patients with type 2 diabetes usually have less severe insulin defi-
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ciency than type 1 patients and the symptoms and signs at presen-
Weight loss, despite normal or increased appetite, is a common
tation reflect this difference.
feature of type 1 diabetes when it develops subacutely over a
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period of weeks. The weight loss is initially due to depletion of

water, glycogen, and triglyceride stores. Chronic weight loss due A. Symptoms Many patients with type 2 diabetes have an
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to reduced muscle mass occurs as amino acids are diverted to form insidious onset of hyperglycemia and may be relatively asymptom-
glucose and ketone bodies. atic initially. The diagnosis may be made only after glycosuria or
Lowered plasma volume produces dizziness and weakness due hyperglycemia is noted during routine laboratory studies. Chronic
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to postural hypotension when sitting or standing. Total body skin infections are common. Generalized pruritus and symptoms
potassium loss and the general catabolism of muscle protein con- of candidal vaginitis are frequently the initial complaints of
women with type 2 diabetes. Men may complain of an itchy rash
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tribute to the weakness.

Paresthesias may be present at the time of diagnosis of type 1 of the prepuce. Some patients can remain undiagnosed for many
years and the initial presentation may be due to complications
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diabetes, particularly when the onset is subacute. They reflect a

temporary dysfunction of peripheral sensory nerves and usually such as visual disturbance due to retinopathy or foot pain or infec-
clear, as insulin replacement restores glycemic levels closer to nor- tion due to a peripheral neuropathy. Patients with a more severe
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mal; thus, their presence suggests neurotoxicity from sustained insulin deficiency have the classical symptoms of polyuria, thirst,
blurred vision, paresthesias, and fatigue. This is especially true in
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hyperglycemia.
When insulin deficiency is severe and of acute onset, the above individuals who consume large amounts of carbohydrate-rich
symptoms progress in an accelerated manner. Ketoacidosis exacer- fluids in response to the thirst.
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bates the dehydration and hyperosmolality by producing anorexia,

nausea, and vomiting, thus interfering with oral fluid replace- B. Signs Many patients are obese or overweight. Even those
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ment. As plasma osmolality exceeds 330 mOsm/kg (normal, 285- patients who are not significantly overweight often have a charac-
295 mOsm/kg), impaired consciousness ensues. With progression teristic fat distribution with more fat in the upper part of the body
of acidosis to a pH of 7.1 or less, deep breathing with a rapid (particularly the abdomen, chest, neck, and face) and relatively
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ventilatory rate (Kussmaul respiration) occurs as the body attempts less fat on the appendages, which may be quite muscular (the
to eliminate carbonic acid. With worsening acidosis (to pH 7.0 or metabolically obese). This centripetal fat distribution has been
less), the cardiovascular system may be unable to maintain com- termed android and is characterized by a high waist circumfer-
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pensatory vasoconstriction; severe circulatory collapse may result. ence. It differs from the more centrifugal gynecoid form of obe-
sity, in which fat is localized more in the hips and thighs and less
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B. Signs The patient’s level of consciousness can vary depend- in the upper parts of the trunk. A larger waist circumference
ing on the degree of hyperosmolality. When insulin deficiency increases the risk for diabetes for any given BMI. Thus in patients
develops relatively slowly and sufficient water intake is maintained with the metabolic syndrome, a waist circumference more than 40
to permit renal excretion of glucose and appropriate dilution of in (102 cm) in men and more than 35 in (88 cm) in women is
extracellular sodium chloride concentration, patients remain rela- associated with an increased risk of diabetes. MRI and CT scans
tively alert and physical findings may be minimal. When vomiting reveal that these patients with increased waist circumference have
occurs in response to worsening ketoacidosis, dehydration pro- accumulation of fat in the omental and mesenteric distributions.
gresses and compensatory mechanisms become inadequate to keep This visceral fat correlates with insulin resistance, whereas fat pre-
plasma osmolality below 330 mOsm/kg. Under these circum- dominantly in subcutaneous tissues of the abdomen has little, if
stances, stupor or even coma may occur. Evidence of dehydration any, association with insulin insensitivity.

Some patients, especially the obese, may have acanthosis rapid, convenient, and glucose specific. This method consists of
nigricans—hyperpigmented, hyperkeratotic skin in the axilla, paper strips (Clinistix, Tes-Tape) impregnated with enzymes (glu-
groin, and back of neck. This sign is associated with significant cose oxidase and hydrogen peroxidase) and a chromogenic dye
insulin resistance. Hypertension may be present especially in the that is colorless in the reduced state. Enzymatic generation of
obese patient. Eruptive xanthomata on the flexor surface of the hydrogen peroxide oxidizes the dye to produce colors whose inten-
limbs and on the buttocks and lipemia retinalis due to hyperchy- sity depends on the glucose concentration. These dipsticks are
lomicronemia can occur in patients with uncontrolled type 2 sensitive to as little as 0.1% glucose (100 mg/dL) but do not react
diabetes who also have a familial form of hypertriglyceridemia. In with the smaller amounts of glucose normally present in nondia-
women, candidal vaginitis with a reddened, inflamed vulvar area betic urine. The strips are subject to deterioration if exposed to air,
and a profuse whitish discharge may herald the presence of diabe- moisture, and extreme heat and must be kept in tightly closed
tes. In men, candidal infection of the penis may lead to reddish containers except when in use. False-negative results may be
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appearance of the penis and/or prepuce with eroded white papules obtained in the presence of alkaptonuria and when certain sub-
and a white discharge. The occasional patient who has had undi- stances such as salicylic acid or ascorbic acid are ingested in excess.
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agnosed diabetes for some time may present with retinopathy or All these false-negative results occur because of the interference of
peripheral neuropathy. strong reducing agents with oxidation of the chromogen.
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Patients can also present in hyperglycemic hyperosmolar Although glycosuria reflects hyperglycemia in more than 90%
coma—profoundly dehydrated, hypotensive, lethargic, or coma- of patients, two major classes of nondiabetic glycosuria must be
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tose without Kussmaul respirations. considered:
A. Alterations in renal handing of glucose Disorders

Laboratory Testing in Diabetes Mellitus
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associated with abnormalities in renal glucose handling include

Tests of urine glucose and ketone bodies, as well as whole blood or Fanconi syndrome, a group of disorders characterized by com-
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plasma glucose measured in samples obtained under basal condi- bined renal wasting of multiple solutes including amino acids, uric
tions and after glucose administration, are very important in acid, phosphate, and bicarbonate as well as glucose and caused by
evaluation of the patient with diabetes. Tests for glycosylated both genetic and acquired defects of the proximal renal tubule.
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hemoglobin have proved useful in both initial evaluation and in Familial renal glycosuria, a benign inherited disorder manifest
assessment of the effectiveness of therapeutic management. In only by persistent glycosuria in the setting of euglycemia is caused
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certain circumstances, measurements of insulin or C-peptide lev- by mutations in SGLT2, the sodium-glucose cotransporter
els and levels of other hormones involved in carbohydrate homeo- responsible for the bulk of glucose reabsorption in the proximal
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stasis (eg, glucagon, GH) may be useful. In view of the increased tubule.
risk of atherosclerosis in patients with diabetes, determination of In addition, glycosuria is relatively common in pregnancy as a
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serum total cholesterol, HDL-cholesterol, triglycerides, and LDL- consequence of the increased load of glucose presented to the
cholesterol may be helpful. tubules by the elevated glomerular filtration rate during pregnancy.
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As many as 50% of pregnant women normally have demonstrable

Urine Glucose sugar in the urine, especially after the first trimester.
Several problems are associated with using urine glucose as an
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B. Excretion of sugars other than glucose in the urine

index of blood glucose, regardless of the method employed. First Occasionally, a sugar other than glucose is excreted in the urine.
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of all, the glucose concentration in bladder urine reflects the blood Lactosuria during the late stages of pregnancy and the period of
glucose at the time the urine was formed. Therefore, the first lactation is the most common example. Much rarer are other con-
voided specimen in the morning contains glucose that was ditions in which inborn errors of metabolism allow fructose,
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excreted throughout the night and does not reflect the morning galactose, or a pentose (1-xylose) to be excreted in the urine. Test-
blood glucose at all. Some improvement in the correlation of urine ing the urine with glucose-specific strips helps differentiate true
glucose to blood glucose can be obtained if the patient double glucosuria from other glycosurias.
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voids—that is, empties the bladder completely, discards that sam-

ple, and then urinates again about one-half hour later, testing only
Microalbuminuria and Proteinuria
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the second specimen for glucose content. However, difficulty in

completely emptying the bladder (large residual volumes), prob- Urinary albumin can now be detected in microgram concentra-
lems in understanding the instructions, and the inconvenience tions using high-performance liquid chromatography or immuno-
impair the usefulness of this test. Self-monitoring of blood glucose assay methodology that is more sensitive than previous available
has replaced urine glucose testing in most patients with diabetes tests. Conventional 24-hour urine collections, in addition to being
(particularly those receiving insulin therapy). inconvenient for patients, also show wide variability of albumin
Several commercial products are available for determining the excretion, because several factors such as sustained upright pos-
presence and amount of glucose in urine. The older and more ture, dietary protein, and exercise tend to increase albumin excre-
cumbersome bedside assessment of glycosuria with Clinitest tab- tion rates. For these reasons, it is preferable to measure the
lets has generally been replaced by the dipstick method, which is albumin-creatinine ratio in an early morning spot urine collected

on awakening—prior to breakfast or exercise—and brought in by TABLE 17–11 Criteria for the diagnosis of diabetes.
the patient for laboratory analysis. A ratio of albumin (μg/L) to
creatinine (mg/L) of less than 30 is normal, and a ratio of 30 to Normal
300 indicates abnormal microalbuminuria. Values greater than Glucose Diabetes
Tolerance Prediabetes Mellitusa
300 are referred to as macroalbuminuria.
The minimal detection limit of protein on a standard urine Fasting plasma <100 (5.6) 100-125 (5.6-6.9) ≥126 (7.0)
glucose mg/ (impaired fasting
dipstick is 10 to 20 mg/dL. If the dipstick is positive then it is dL(mmol/L)b glucose)
likely that the patient has microalbuminuria and this should be
2 h after glucose <140 (7.8) ≥140-199 ≥200 (11.1)
specifically tested. The information from a spot urine sample is load mg/dL (7.8-11.0)
adequate for diagnosis and treatment and it is not usually neces- (mmol/L)c (impaired glucose
sary to perform a 24-hour urine collection for protein loss and tolerance)
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creatinine clearance. HbA1c (%)a <5.7 5.7-6.4 ≥6.5

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Symptoms and – – ≥200

Blood Glucose Testing random glu-
cose level
A. Venous blood samples in the laboratory Venous glu- (mg/dL)
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cose samples should be collected in tubes containing sodium fluo- a

A fasting plasma glucose or HbA1c is diagnostic of diabetes if confirmed by repeat
ride, which inhibits enolase and prevents glycolysis in the blood
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testing. HbA1c test should be performed using an assay certified by the National
sample that would artifactually lower the measured glucose level. Glycohemoglobin Standardization program and standardized to the DCCT assay.
b
In the absence of fluoride, the rate of disappearance of glucose in the A fasting plasma glucose ≥126 mg/dL is diagnostic of diabetes if confirmed on a
subsequent day to be in the diabetic range after an overnight fast.
presence of blood cells has been reported to average 10 mg/dL/h—
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Give 75 g of glucose dissolved in 300 mL of water after an overnight fast in subjects
the rate increases with glucose concentration, temperature, and who have been receiving at least 150 to 200 g of carbohydrate daily for 3 days before
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white blood cell count. Fluoride takes about 1 hour to effectively the test. In the absence of unequivocal hyperglycemia, the result should be con-
firmed by repeat testing.
stop glycolysis. Therefore, the rate of decline during the first hour
is the same in tubes with or without fluoride. A very high white
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blood cell count will lower glucose levels even in the presence of
fluoride. Ideally the blood should be collected in a sodium fluoride/ to oxidize a chromogen or the consumption of oxygen measured
potassium oxalate tube, placed on ice and the plasma separated
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to estimate the amount of glucose present. Current laboratories

from the cells within 60 minutes. use enzymatic methods to determine glucose levels.
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Plasma or serum from venous blood samples has the advantage The range of normal fasting plasma or serum glucose is 70 to
over whole blood of providing values for glucose that are indepen- 100 mg/dL (3.9-5.5 mmol/L). A plasma glucose level of 126 mg/dL
dent of hematocrit and reflect levels in the interstitial spaces to (7.0 mmol/L) or higher on more than one occasion after at least
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which body tissues are exposed. For these reasons—and 8 hours of fasting is diagnostic of diabetes mellitus (Table
because plasma and serum lend themselves to automated analytic 17–11). Fasting plasma glucose levels of 100 mg/dL (5.6 mmol/L)
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procedures—they are used in most laboratories. The glucose con- to 125 mg/dL (6.9 mmol/L) are associated with increased risk for
centration is 10% to 15% higher in plasma or serum than in diabetes (impaired fasting glucose).
whole blood because structural components of blood cells are
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absent. Whole blood glucose determinations are seldom used in B. Self monitoring of blood glucose Capillary blood glu-
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clinical laboratories, but are used by patients using home blood cose measurements performed by patients themselves, as outpa-
glucose monitors. tients, are extremely useful. In type 1 patients in whom tight
Glucose levels can be measured in the laboratory using enzy- metabolic control is attempted, they are indispensable. There are
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matic methods (such as glucose oxidase or hexokinase), condensa- several paper strip (glucose oxidase; hexokinase; glucose dehydro-
tion methods (such as o-toluidine), or reducing methods. The genase with nicotinamide adenine dinucleotide, glucose dehydroge-
reducing methods take advantage of the reducing properties of nase with flavin-adenine dinucleotide, glucose dehydrogenase with
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glucose to change the redox state of a metal ion; however, the pyrroloquinoline quinine) methods for measuring glucose on capil-
method is nonspecific and any strong reducing agent can cross- lary blood samples. A reflectance photometer or an amperometric
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react to yield spuriously elevated glucose values. In condensation system is then used to measure the reaction that takes place on the
methods, the aldehyde group of glucose undergoes condensation reagent strip. A large number of blood glucose meters are now
with aromatic compounds to yield a colored product. In the most available. All are accurate, but they vary with regard to speed, con-
commonly used condensation reaction, o-toluidine reacts with venience, size of blood samples required, and cost. Popular models
glucose to form a glucosamine that has an intense green color. The include those manufactured by Life-Scan (One Touch), Bayer
color is measured spectrophotometrically to estimate the glucose Corporation (Breeze, Contour), Roche Diagnostics (Accu-Chek),
concentration. o-Toluidine, however, has the drawback of being and Abbott Laboratories (Precision, FreeStyle). Various glucome-
highly corrosive and toxic. In the enzymatic method, glucose oxi- ters appeal to a particular consumer need and are relatively inex-
dase reacts with glucose, water, and oxygen to form gluconic acid pensive, ranging from $50.00 to $100.00 (U.S.) each. Test strips
and hydrogen peroxide. The hydrogen peroxide can then be used remain a major expense, costing $0.25 to $1.50 (U.S.) each.

The meters have memories and can compute blood glucose the glucose data are displayed. The MiniMed system can only be
averages. The data can be downloaded into a computer. Some used in conjunction with the MiniMed pump and the glucose
meters are designed to communicate with a specific insulin pump. data are displayed on the screen of the pump. The DexCom sys-
Contour Next Link meter, for example, communicates with the tem wirelessly transmits glucose data to a separate pager-like
MiniMed Medtronic pump. In self-monitoring of blood glucose, device with a screen. The DexCom system also has the option of
patients must prick a finger with 26- to 33-gauge lancets. This can having the data appear on smart phones or smart watches or on
be facilitated by a small plastic trigger device such as an Accu- the screens of several insulin pumps. The FreeStyle Libre (Abbott
Chek multiclix (Roche Diagnostics), Microlet (Boehringer- Diagnostics) sensor system requires the patient to hold a reading
Mannheim), or one touch lancing device (Lifescan, Inc.). device close to the sensor patch for about a second to see the real
The clinician should be aware of the limitations of the self- time glucose value. The MiniMed and DexCom systems also dis-
glucose monitoring systems. The strips have limited lifespans and play directional arrows indicating rate and direction of change and
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improper storage (high temperature; open vial) can affect their alarms can be set for dangerously low or high glucose values.
function. Patients should also be advised not to use expired strips. Patients still have to calibrate the MiniMed and DexCom devices
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Some of the older meters require input of a code for each batch of with periodic fingerstick glucose levels, and since there are con-
strips and failure to enter the code can result in misleading results. cerns regarding reliability, it is still necessary to confirm the dis-
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Most meters no longer require this step. Increases or decreases in played glucose level with a fingerstick glucose before making
hematocrit can decrease or increase the measured glucose values, interventions such as injecting extra insulin or eating extra carbo-
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respectively. The mechanism underlying this effect is not known, hydrates. The FreeStyle Libre system does not require calibration
but presumably it is due to the impact of red cells on the diffusion and glucose readings are available 1 hour after insertion of sensors.
of plasma into the reagent layer. Meters and the test strips are cali- The glucose data can be downloaded into computers for review by
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brated over glucose concentrations ranging from 60 to 160 mg/dL, patients and their medical providers.
and the accuracy is not as good for higher and lower glucose levels. A 6-month randomized controlled study of type 1 patients
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Thus, when the glucose is less than 60 mg/dL, the difference showed that adults (25 years and older) using these systems had
between the meter and the laboratory value may be as much as improved glycemic control without an increase in the incidence of
20%. Glucose-oxidase-based amperometric systems underesti- hypoglycemia. A randomized controlled study of CGM during
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mate glucose levels in the presence of high oxygen tension. This pregnancy showed improved glycemic control in the third trimes-
may be important in critically ill patients who are on supplemen- ter, lower birth weight, and reduced risk of macrosomia. The
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tal oxygen, and under these circumstances, a glucose dehydroge- individual glucose values are not that critical—what matters is the
nase-based system may be preferable. Glucose-dehydrogenase direction and the rate at which the glucose is changing, allowing
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pyrroloquinoline quinone (GDH-PQQ) systems may report the user to take corrective action. The wearer also gains insight
falsely high glucose levels in patients who are receiving parenteral into the way particular foods and activities affect their glucose
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products containing nonglucose sugars such as maltose, galactose, levels. The other main benefit is the low glucose alert warning.
or xylose or their metabolites. Some meters have been approved The MiniMed insulin pump can be programmed to automatically
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for measuring glucose in blood samples obtained at alternative suspend insulin delivery for up to 2 hours when the glucose levels
sites such as the forearm and thigh. There is, however, a 5- to on its CGM device falls to a preset level and the patient does not
20-minute lag in the glucose response on the arm with respect to respond to the alert. This insulin suspension feature has been
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the glucose response on the finger. Forearm blood glucose mea- shown to reduce the amount of time patients are in the hypogly-
surements could therefore result in a delay in detection of rapidly cemic range at night. Many of these systems are covered by insur-
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developing hypoglycemia. Impaired circulation to the fingers (for ance. The initial cost is about $800 to $1000, and the sensor,
example, in patients with Raynaud’s disease) will artificially lower which has to be changed every 3 to 14 days, costs $35 to $77; the
finger-stick glucose measurements (pseudohypoglycemia). The out-of-pocket expense is about $4000 annually.
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accuracy of data obtained by glucose monitoring requires educa- There is great interest in using the data obtained from these
tion of the patient in sampling and measuring procedures as well CGM systems to automatically deliver insulin by continuous sub-
as in proper calibration of the instruments. Bedside glucose moni- cutaneous insulin infusion pump. Algorithms have been devised
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toring in a hospital setting requires rigorous quality control pro- to link CGM to insulin delivery. These closed loop systems (arti-
grams and certification of personnel to avoid errors. ficial pancreas) have been shown in short-term clinical studies to
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improve night time glucose control and reduce the risk of noctur-
Continuous Glucose Monitoring Systems nal hypoglycemia. The first of these closed loop systems (MiniMed
system) has been approved for clinical use. With this system, the
A number of continuous glucose monitoring (CGM) systems are continuous glucose monitor readings are used to automatically
currently available for clinical use. The systems manufactured by adjust basal insulin rates by the insulin pump.
Medtronic MiniMed, DexCom, Abbott Diagnostics involve
inserting a subcutaneous biosensor (rather like an insulin pump
cannula) that measures glucose concentrations in the interstitial Urine and Serum Ketone Determinations
fluid for 3 to 14 days. The glucose values are available for review In the absence of adequate insulin, three major ketone bodies are
by the patient at time of measurement. The systems differ in how formed and excreted into the urine: β-hydroxybutyrate (often the

most prevalent in diabetic ketoacidosis), acetoacetate, and ace- and this explains why significant changes in HbA1c are observed
tone. Acetone and acetoacetate react with sodium nitroprusside with short-term (1 month) changes in mean plasma glucose
(nitroferricyanide) in the presence of alkali to produce a purple- levels. Measurements should be made in patients with either
colored complex. Ketone test strips (ketostix; Keto-Diastix) utilize type of diabetes mellitus at 3- to 4-month intervals so that
this nitroprusside reaction to quantify acetone and acetoacetate adjustments in therapy can be made if GHb is either subnormal
levels in urine and plasma. A strongly positive reaction in undiluted or if it is more than 1% above the upper limits of normal for a
serum correlates with a serum ketone concentration of at least particular laboratory. In patients monitoring their own blood
4 mmol/L. Although these tests do not detect β-hydroxybutyric glucose levels, GHb values provide a valuable check on the accu-
acid, which lacks a ketone group, the semiquantitative estimation racy of monitoring. In patients who do not monitor their own
of the other ketone bodies is nonetheless usually adequate for blood glucose levels, GHb values are essential for adjusting
clinical assessment of ketonuria. Ketostix and Keto-Diastix have therapy.
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short shelf-lives (90 days) once the containers are opened and The various HbA1c assays have been standardized to the assay
using expired strips can give false-negative results. It is better used in the Diabetes Control and Complications Trial (DCCT)
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therefore to buy individually foil wrapped strips. allowing the results to be related to the risks of developing micro-
Many laboratories measure β-hydroxybutyrate levels and there vascular complications. There is a linear relationship between the
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are meters available (Precision Xtra, Nova Max Plus) for patients HbA1c value and average glucose. The A1c-Derived Average Glu-
to measure β-hydroxybutyrate levels on capillary glucose samples. cose Study collected 3 months of blood glucose data on 507
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This technology uses hydroxybutyrate dehydrogenase to catalyse subjects—normals, type 1 and type 2 diabetics. The estimated
the oxidation of β-hydroxybutyrate to acetoacetate with concomi- average glucose was calculated by combining weighted results
tant reduction of NAD+ to NADH. The NADH is reoxidized to from 2 days of CGM per month and seven point capillary blood
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NAD+ by a redox mediator and a current is generated that is glucose profiles (preprandial, postprandial, and bedtime) for at
directily proportional to β-hydroxybutyrate concentration. least 3 days/wk. The HbA1c was measured at the end of the
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β-Hydroxybutyrate levels more than 0.6 nmol/L require evalua- 3 months. The relationship between average glucose and HbA1c
tion. Levels more than 3.0 nmol/L, which is equivalent to very based on linear regression analysis was Average glucose = (28.7 ×
large urine ketones, will require hospitalization. HbA1c) – 46.7. There is, however, substantial intra-individual
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Other conditions besides diabetic ketoacidosis may cause variability. For HbA1c values between 6.9% and 7.1%, the glucose
ketone bodies to appear in the urine; these include starvation, levels ranged from 125 to 205 mg/dL (6.9-11.4 mmol/L; 95%
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high-fat diets, alcoholic ketoacidosis, fever, and other conditions CIs). For HbA1c of 6%, the mean glucose levels ranged from 100 to
in which metabolic requirements are increased. 152 mg/dL (5.5-8.5 mmol/L); and for 8% they ranged from 147 to
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217 mg/dL (8.1-12.1 mmol/L).

The accuracy of HbA1c values can be affected by hemoglobin
Glycated Hemoglobin Assays
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variants or derivatives, the effect depending on the specific hemo-

Ketoamine reactions between glucose and other sugars and free globin variant or derivative and the specific assay used. Immuno-
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amino groups on the alpha and beta chain lead to glycated forms assays that use an antibody to the glycated amino terminus of
of hemoglobin. Only glycation of the N-terminal valine of the β globin do not recognize the terminus of the γ globin of hemoglo-
beta chain imparts sufficient negative charge to the hemoglobin bin F, and so in patients with high levels of hemoglobin F, immu-
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molecule to allow separation by charge-dependent techniques. noassays give falsely low estimates of HbA1c. Cation exchange
The charge-separated hemoglobins are collectively referred to as chromatography separates hemoglobin species by charge differ-
up
hemoglobin A1 (HbA1). The major form of HbA1 is hemoglobin ences. Therefore, hemoglobin variants that coelute with HbA1c can
A1c (HbA1c), where glucose is the carbohydrate. This form com- lead to an overestimation of the HbA1c value. Chemically modified
prises 4% to 6% of total hemoglobin A. The remaining HbA1 derivatives of hemoglobin such as carbamylated (in renal failure) or
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species contain fructose 1,6-diphosphate (HbA1a1), glucose acetylated (high-dose aspirin therapy) hemoglobin can, in some
6-phosphate (HbA1a2), and an unknown carbohydrate moiety methods, coelute with HbA1c. Since many hemoglobin variants do
(HbA1b). The hemoglobin A1c fraction is abnormally elevated in not have a clinical phenotype, they should be considered if there is
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diabetic patients with chronic hyperglycemia. Some laboratories discordance between home blood glucose and HbA1c measure-
measure the sum of these glycohemoglobins (GHbs) and report ments. The National Glycohemoglobin Standardization Program
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the total as hemoglobin A1, but most laboratories have converted website (www.ngsp.org) has information on the impact of fre-
to the highly specific HbA1c assay. Methods for measuring HbA1c quently encountered hemoglobin variants and traits on the results
include electrophoresis, cation exchange chromatography, boro- obtained with the commonly used HbA1c assays.
nate affinity chromatography, and immunoassays Office-based Any condition that shortens erythrocyte survival or decreases
immunoassays using capillary blood give a result in about 9 minutes, mean erythrocyte age (eg, recovery from acute blood loss, hemo-
and this allows for immediate feedback to the patients regarding lytic anemia) falsely lower HbA1c irrespective of the assay method
their glycemic control. used. Alternative methods such as fructosamine (discussed later)
The red cell lifespan is about 120 days and so HbA 1c levels should be considered for these patients. Vitamins C and E are
reflect glucose levels in the preceding 8 to 12 weeks. The value, how- reported to falsely lower test results, possibly by inhibiting glyca-
ever, is weighted to more recent glucose levels (previous month) tion of hemoglobin. The American Diabetes Association (ADA)

has now endorsed using the HbA1c as a diagnostic test for diabetes be considered, for example, in a woman with a history of deliver-
(see Table 17–11). A cutoff value of 6.5% was chosen because the ing an infant above 9 lb (4.1 kg).
risk for retinopathy increases substantially above this value. The In order to optimize insulin secretion and effectiveness, espe-
advantages of using the HbA1c to diagnose diabetes is that there is cially when patients have been on a low-carbohydrate diet, a mini-
no need to fast; it has lower intra-individual variability than the mum of 150 to 200 g of carbohydrate per day should be included
fasting glucose test and the oral glucose tolerance test; and it gives in the diet for 3 days preceding the test. The patient should eat
a better picture of glucose control for 2 to 3 months. People with nothing after midnight prior to the test day. Adults are given 75 g
HbA1c levels of 5.7 % to 6.4% should be considered at high risk of glucose in 300 mL of water; children are given 1.75 g of glucose
for developing diabetes (prediabetes). The diagnosis should be per kilogram of ideal body weight. The glucose load is consumed
confirmed with a repeat HbA1c test, unless the patient is symp- within 5 minutes. The test should be performed in the morning
tomatic with plasma glucose levels more than 200 mg/dL. This because there is some diurnal variation in oral glucose tolerance
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test would not be appropriate to use in populations with high and patients should not smoke; drink coffee, tea, or alcohol; or be
prevalence of hemoglobinopathies or in conditions with increased active during the test.
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red cell turnover. Also, the testing should be performed using a Blood samples for plasma glucose are obtained at 0 and 120
National Glycohemoglobin Standardization Program certified minutes after ingestion of glucose. A fasting plasma glucose
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method and standardized to the Diabetes Control and Complica- value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of
tions Trial assay. In the Europeon Union, the tests are standardized greater than 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes
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to the International Federation of Clinical Chemistry (IFCC) mellitus (see Table 17–11). An oral glucose tolerance test is
which defines HbA1c as mmol glycated hexapeptide per mol (gly- normal if the fasting venous plasma glucose value is less than
cated and nonglycated hexapeptides) and reported as mmol 100 mg/dL (5.6 mmol/L) and the 2-hour value falls below 140 mg/dL
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HbA1c/mol Hb. The conversion factor for NGSP and IFCC (7.8 mmol/L). Patients with 2-hour values of 140 to 199 mg/dL
results is: NGSP (USA) result = (0.09148 × IFCC result) + 2.152. have impaired glucose tolerance. False-positive results may occur
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Officially there is worldwide consensus that HbA1c should be in patients who are malnourished at test time, bedridden, or
reported in both NGSP (%) and IFCC (mmol/mol) units. afflicted with an infection or severe emotional stress. Diuretics,
oral contraceptives, glucocorticoids, excess thyroxine, phenyt-
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Serum Fructosamine oin, nicotinic acid, and some of the psychotropic drugs may also
cause false-positive results.
Serum fructosamine is formed by nonenzymatic glycosylation of
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serum proteins (predominantly albumin). Because serum albumin

has a much shorter half-life (14-21 days) than hemoglobin, serum Insulin Levels
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fructosamine generally reflects the state of glycemic control for the Normal immunoreactive insulin levels range from 5 to 20 μU/mL
preceding 2 or 3 weeks. Reductions in serum albumin (eg, in the fasting state. During an oral glucose tolerance test, they
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nephrotic state or hepatic disease) lower the serum fructosamine reach 50 to 130 μU/mL at 1 hour, and usually return to levels
value. When abnormal hemoglobins or hemolytic states affect the below 30 μU/mL by 2 hours. Insulin measurements are rarely of
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interpretation of GHb or when a narrower time frame is required, clinical usefulness. They are principally used in research studies to
such as for ascertaining glycemic control at the time of conception determine insulin sensitivity.
in a woman with diabetes who has recently become pregnant, The homeostasis model of insulin resistance (HOMAIR) esti-
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serum fructosamine assays offer some advantage. Normal values mates insulin sensitivity using the following formula:
vary in relation to the serum albumin concentration and are 200
up
to 285 umol/L when the serum albumin level is 5 g/dL. HbA1c HOMAIR (mmol/L × μU/mL) = (fasting glucose [mmol/L]
values and fructosamine are highly correlated. × fasting insulin [μU/mL])/22.5
Thus fructosamine levels of 300, 367, and 430 approximate to
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HbA1c values of 7%, 8%, and 9%, respectively but there is sub- The higher the HOMAIR value the more resistant the indi-
stantial individual variability and caution should be exercised in vidual. Data from the oral glucose tolerance test can also be used
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estimating the likely HbA1c value from the fructosamine to estimate insulin sensitivity. The Matsuda & DeFronzo Insulin
measurement. Sensitivity Index is calculated as:
In most circumstances, glycohemoglobin assays remain the
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preferred method for assessing long-term glycemic control in Insulin sensitivity index (ISI)
patients with diabetes. = 10,000/square root of [fasting glucose × fasting insulin]
× [mean glucose × mean insulin during OGTT]
Oral Glucose Tolerance Test
The lower the ISI the more insulin resistant the subject.
It is easy to screen for diabetes using an HbA1c or a fasting plasma
glucose level (see Table 17–11). The oral glucose tolerance test,
therefore, is mostly performed for research studies or when there Intravenous Glucose Tolerance Test
is a suspicion of the diagnosis but the fasting plasma glucose is less The intravenous glucose tolerance test (IVGTT) is performed by
than 126 mg/dL or the HBA1c level is below 6.5%. The test might giving a bolus of 50 g of glucose per 1.7 m2 body surface area

(or 0.5 g/kg of ideal body weight) as a 25% or 50% solution over hypoglycemic therapy substantially correct the dyslipidemia but
2 to 3 minutes after an overnight fast. Timing begins with injec- most patients require pharmacotherapy. Chapter 19 discusses
tion and samples for plasma glucose determination are obtained these matters in detail.
from an indwelling needle in the opposite arm at 0, 10, 15, 20,
and 30 minutes. The plasma glucose values are plotted on semi- Clinical Trials in Diabetes
logarithmic paper against time. K, a rate constant that reflects the
Findings of the Diabetes Control and Complications Trial
rate of fall of blood glucose in percent per minute, is calculated by
(DCCT) and of the United Kingdom Prospective Diabetes Study
determining the time necessary for the glucose concentration to
(UKPDS) have confirmed the beneficial effects of intensive ther-
fall by one-half (t1/2) and using the following equation:
apy to achieve improved glycemic control in both type 1 and type
0.693 2 diabetes, respectively.
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K (glucose) = × 100
t1/2
A. The Diabetes Control and Complications Trial (DCCT),
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The average K value for a nondiabetic patient is approximately a long-term therapeutic study involving 1441 patients with type 1
1.72% per minute; this value declines with age but remains above diabetes mellitus, reported that “near” normalization of blood
glucose resulted in a delay in the onset and a major slowing of the
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1.3% per minute. Patients with diabetes almost always have a K

value of less than 1% per minute. The disappearance rate reflects progression of established microvascular and neuropathic compli-
cations of diabetes during a follow-up period of up to 10 years.
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the patient’s ability to dispose of a glucose load. Perhaps its most

widespread present use is to screen siblings at risk for type 1 diabe- Multiple daily insulin injections (66%) or insulin pumps (34%)
tes to determine if autoimmune destruction of β cells has reduced were used in the intensively treated group whereas the convention-
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first phase insulin responses (at 1-5 minutes after the glucose bolus) ally treated group used no more than two injections daily. The
to levels below the normal lower limit of 40 μU/mL. intensive group achieved a mean HbA1c of 7.2% (normal: <6%)
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The IVGTT has been modified by giving a glucose dose of and a mean blood glucose of 155 mg/dL (8.6 mmol/L) while the
0.3 g/kg, with more frequent plasma sampling and extending the conventionally treated group averaged an HbA1c of 8.9% and
test to 3 to 4 hours. Also at 20 minutes, a 5-minute infusion of mean blood glucose of 225 mg/dL (12.5 mmol/L). Over mean
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insulin is given (0.03 U/kg for the subject who is likely to be follow-up of 7 years, there was an approximately 60% reduction
insulin sensitive and 0.06 U/kg for the likely resistant subject). in risk between the two groups in regard to diabetic retinopathy,
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Plasma glucose is sampled at 3, 4, 5, 6, 8, 10, 14, 19, 22, 25, 27, nephropathy, and neuropathy. The intensively treated group also
30, 40, 50, 60, 80, 100, 140, and 180 minutes. Analysis of the had a nonsignificant reduction in the risk of macrovascular disease
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time course of glucose and insulin during this frequently sampled of 41% (95% CI, –10 to 68). Intensively treated patients had a
IVGTT (FSIVGTT) allows for measurements of insulin sensitiv- threefold greater risk of serious hypoglycemia as well as a greater
tendency toward weight gain. However, there were no deaths defi-
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ity (Si), that is, fractional glucose clearance per unit insulin con-
centration; the first phase insulin response (AIRglucose); and glucose nitely attributable to hypoglycemia in any persons in the DCCT
study, and no evidence of posthypoglycemic cognitive damage was
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effectiveness (SG), the ability of glucose itself to enhance its own

disappearance independent of any change in insulin. The data detected.
analysis requires use of specific software (Minmod). Subjects participating in the DCCT study were subsequently
enrolled in a follow-up observational study (Epidemiology of Dia-
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betes Interventions and Complications [EDIC]). Even though the

Lipoproteins in Diabetes
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between group differences in HbA1c narrowed within 4 years, the

Levels of circulating lipoproteins are dependent on normal levels group assigned to intensive therapy had a lower risk for retinopa-
and action of insulin, just as is the plasma glucose. In type 1 dia- thy at 4 years and microalbuminuria at 7 to 8 years of post study
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betes, moderately deficient control of hyperglycemia is associated follow-up. Moreover, by the end of the 11 year follow-up period,
with only a slight elevation of low-density lipoprotein (LDL) the intensive therapy group had significantly reduced risk of any
cholesterol and serum triglycerides and little if any changes in cardiovascular disease events by 42% (95% CI, 9%-23%; p =
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HDL cholesterol. Once the hyperglycemia is corrected, lipopro- 0.02). Thus it seems that the benefits of good glucose control
tein levels are generally normal. However, patients with type 2 persist even if control deteriorates at a later date.
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diabetes frequently have a dyslipidemia that is characteristic of the The general consensus of the ADA is that intensive insulin
insulin resistance syndrome. Its features are a high serum triglyc- therapy associated with comprehensive self-management training
eride level (300-400 mg/dL), a low HDL cholesterol (<30 mg/dL), should become standard therapy in most patients with type 1 dia-
and a qualitative change in LDL particles producing a smaller betes after the age of puberty. Exceptions include those with
dense LDL whose membrane carries supranormal amounts of advanced renal disease and the elderly, because the detrimental risks
free cholesterol. Because low HDL cholesterol is a major feature of hypoglycemia outweigh the benefit of tight glycemic control in
predisposing to macrovascular disease, the term dyslipidemia these groups. In children under age 7 years, the risk of developing
has preempted the previous label of hyperlipidemia, which brain damage from hypoglycemia contraindicates attempts at tight
mainly described the elevated triglycerides. Measures designed to glycemic control, particularly because diabetic complications do not
correct obesity and hyperglycemia, such as exercise, diet, and seem to occur until some years after the onset of puberty.

B. The United Kingdom Prospective Diabetes Study demonstrable advantage of ACE inhibitor therapy over beta
(UKPDS) was a multicenter study designed to determine blockers as regards diabetes endpoints. Use of a calcium channel
whether the risk of macrovascular or microvascular complications blocker added to both treatment groups appeared to be safe over
in patients with type 2 diabetes could be reduced by intensive the long term in this population with diabetes, despite some con-
blood glucose control with oral hypoglycemic agents or insulin troversy in the literature about its safety in such individuals.
and whether any particular therapy was better than the others. The UKPDS researchers, like the DCCT group, performed
Patients aged 25 to 65 years who were newly diagnosed with type posttrial monitoring to determine if there were long-term benefits
2 diabetes were recruited between 1977 and 1991, and a total of of having been in the intensively treated glucose and blood pres-
3867 were studied over 10 years. The median age at baseline was sure arms of the study. The between group differences in HbA1c
54 years; 44% were overweight (>20% over ideal weight), and were lost within the first year of follow-up but the reduced risk of
baseline HbA1c was 9.1%. Therapies were randomized to include development or progression of microvascular complications in the
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a control group on diet alone and separate groups intensively intensively treated group persisted for 10 years (24%, p = 0.001).
The intensively treated group also had significantly reduced risk
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treated with insulin, chlorpropamide, glyburide, or glipizide. Met-

formin was included as a randomization option in a subgroup of for myocardial infarction (15%, p = 0.01) and death from any
342 overweight patients, and—much later in the study—an addi- cause (13%, p = 0.007) during the follow-up period. The sub-
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tional subgroup of both normal-weight and overweight patients, group of overweight or obese subjects who were initially random-
who were responding unsatisfactorily to sulfonylurea therapy, were ized to metformin therapy showed sustained reduction in risk of
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randomized to either continue on their sulfonylurea therapy alone myocardial infarction and death from any cause in the follow-up
or to have metformin combined with it. period. The between group blood pressure differences disappeared
After the study was initiated, a further modification was made within 2 years of the end of the trial. Unlike the sustained benefits
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to evaluate whether tight control of blood pressure with stepwise seen with glucose control, there was no sustained benefit from
antihypertensive therapy would prevent macrovascular and micro- having been in the more tightly controlled blood pressure group.
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vascular complications in 758 hypertensive patients among this Both blood pressure groups had similar risks for microvascular
UKPDS population—compared with 390 patients whose blood events and diabetes related endpoints in the follow-up period.
pressure was treated less intensively. The tight control group was Thus, the follow-up of the UKPDS type 2 diabetes cohort
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randomly assigned to treatment with either an angiotensin- showed that, as in type 1 diabetes, the benefits of good glucose
converting enzyme (ACE) inhibitor (captopril) or a beta blocker control persist even if control deteriorates at a later date. Blood
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(atenolol). Both drugs were stepped up to maximum doses of 100 pressure benefits, however, last only as long as the blood pressure
mg/d, and then, if blood pressure remained higher than the target is well controlled.
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level of less than 150/85 mm Hg, more drugs were added in the
following stepwise sequence—a diuretic, slow-release nifedipine, C. Diabetes Prevention Program (DPP) was a random-
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methyldopa, and prazosin—until the target level of tight control ized clinical trial in 3234 overweight men and women, aged 25 to
was achieved. In the control group, hypertension was convention- 85 years, who showed impaired glucose tolerance. Results from
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ally treated to achieve target levels less than 180/105 mm Hg, but this study indicated that intervention with a low-fat diet and 150
these patients were not given either ACE inhibitors or beta minutes of moderate exercise (equivalent to a brisk walk) per week
blockers. reduces the risk of progression to type 2 diabetes by 58% as com-
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Intensive glycemic therapy with either sulfonylureas, metfor- pared with a matched control group. Another arm of this trial
min, combinations of these, or insulin achieved mean HbA1c levels of demonstrated that use of 850 mg of metformin twice daily
up
7.0%. This level of glycemic control decreased the risk of micro- reduced the risk of developing type 2 diabetes by 31% but was
vascular complications in comparison with conventional therapy relatively ineffective in those who were either less obese or in the
(mostly diet alone), which achieved mean levels of HbA1c of 7.9%. older age group.
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Weight gain occurred in intensively treated patients except when

metformin was used as monotherapy. There was a trend toward D. The Steno-2 Study This was designed in 1990 to validate
reduction in cardiovascular events (fatal or nonfatal MI; sudden the efficacy of targeting multiple concomitant risk factors for both
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death) with intensive treatment but this did not reach statistical microvascular and macrovascular disorders in type 2 diabetes. A
significance (16% reduction, p = 0.052). Hypoglycemic reactions prospective, randomized, open, blinded endpoint design was used
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occurred in the intensive treatment groups, but only one death in which 160 patients with type 2 diabetes and microalbuminuria
from hypoglycemia was documented over 27,000 patient years of were assigned to conventional therapy with their general practitio-
intensive therapy. ner or to intensive care at the Steno Diabetes Center. In the inten-
Tight control of blood pressure (median value 144/82 mm Hg sively treated group, stepwise introduction of lifestyle and
vs 154/87 mm Hg) substantially reduced the risk of microvascular pharmacologic interventions was aimed at keeping glycated hemo-
disease and stroke but not myocardial infarction. The blood pres- globin less than 6.5%, blood pressure less than 130/80 mm Hg,
sure lowering had substantially greater impact on microvascular total cholesterol less than 175 mg/dL, and triglycerides less than
outcomes than that achieved by lowering HbA1c from 7.9% to 150 mg/dL. All subjects in the intensively treated group received
7%. More than half of the patients needed two or more drugs for ACE inhibitors and if intolerant, an angiotensin II receptor
adequate therapy of their hypertension, and there was no blocker. The lifestyle component of intensive intervention

included reduction in dietary fat intake to less than 30% of total blood pressure and lipid levels. After a median follow-up of 5.6 years,
calories, a smoking cessation program, light to moderate exercise, there was no significant difference in the primary outcome in the
and a daily vitamin-mineral supplement (vitamins C and E and intensively treated group (HbA1c 6.9%) compared to the standard
chromium picolinate). Initially, aspirin was given as secondary therapy (HbA1c 8.4%). Within this larger study, there was an
prevention to patients with a history of ischemic cardiovascular embedded study evaluating the impact of intensive therapy in
disease, but later all patients received aspirin. patients who were categorized as having low, moderate, and high
After a mean follow-up of 7.8 years, 44% of patients in the coronary calcium scores on CT scans. Patients with low coronary
conventional arm and 24% in the intensive multifactorial arm calcium score showed reduced number of cardiovascular events
developed cardiovascular events (myocardial infarction, angioplas- with intensive therapy.
ties, coronary bypass grafts, strokes, amputations, vascular surgical Thus, the ACCORD, ADVANCE, and VADT results do not
provide support for the hypothesis that near-normal glucose con-
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interventions)—a 53% reduction. Rates of nephropathy, retinopa-

thy, and autonomic neuropathy were also lower in the multifacto- trol in type 2 diabetes will reduce cardiovascular events. It is,
however, important not to over-interpret the results of these three
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rial intervention arm—61%, 58%, and 63% of rates in the

conventional arm, respectively. studies. The results do not exclude the possibility that cardiovas-
The subjects who participated in this trial were subsequently cular benefits might accrue with longer duration of near-normal
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enrolled in an observational follow-up study for an average of glucose control. In the UKPDS, risk reductions for myocardial
5.5 years. Even though the significant differences in glycemic infarction and death from any cause were only observed during
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control and levels of risk factors for cardiovascular disease between 10 years of post-trial follow-up. Specific subgroups of type 2 dia-
the groups had disappeared by the end of the follow-up period, betes patients may also have different outcomes. The ACCORD,
the interventional group continued to have a lower risk for retinal ADVANCE, and VADT studies recruited patients who had diabe-
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photocoagulation, renal failure, cardiovascular endpoints, and tes for 8 to 10 years, and a third of them had established cardio-
cardiovascular mortality. vascular disease. Patients in the UKPDS, in contrast, had newly
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The data from the UKPDS and this study thus provide sup- diagnosed diabetes, and only 7.5% had a history of macrovascular
port for guidelines recommending vigorous treatment of con- disease. It is possible that the benefits of tight glycemic control on
comitant microvascular and cardiovascular risk factors in patients macrovascular events are attenuated in patients with longer dura-
y
with type 2 diabetes. tion of diabetes or with established vascular disease. Specific thera-
pies used to lower glucose may also affect cardiovascular event rate
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E. Accord, Advance, and VADT studies The ACCORD or mortality. Severe hypoglycemia occurred more frequently in the
study was a randomized controlled study designed to determine intensively treated groups of the ACCORD, ADVANCE, and
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whether normal HbA1c levels would reduce the risk of cardiovas- VADT studies; and the ACCORD investigators were not able to
cular events in middle-aged or older individuals with type 2 diabetes. exclude undiagnosed hypoglycemia as a potential cause for the
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About 35% of the 10,251 recruited subjects had established car- increased death rate in their intensive arm group.
diovascular disease at study entry. The intensive arm of the study A formal meta-analysis performed on the raw trial data from
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was discontinued after 3.5 years of follow-up because of more the ACCORD, ADVANCE, VADT, and UKPDS studies found
unexplained deaths in the intensive arm when compared to the that allocation to more intensive glucose control reduced the risk
conventional treatment arm (22%, p = 0.020). Analysis of the data of MI by 15% (hazard ratio 0.85, 95% CI 0.76-0.94). The benefit
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at time of discontinuation showed that the intensively treated appeared to be in patients who did not have preexisting macrovas-
group (HbA1c 6.4%) had a 10% reduction in cardiovascular event cular disease.
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rate compared to the standard treated group (HbA1c 7.5%), but

this difference was not statistically significant. The ADVANCE
trial randomly assigned 11,140 patients in their 60s with type 2 TREATMENT OF DIABETES MELLITUS
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diabetes to standard or intensive glucose control. The primary

outcomes were major macrovascular (nonfatal myocardial infarc- Diet
tion or stroke or death from cardiovascular causes) or microvascu- A well-balanced, nutritious diet remains a fundamental element of
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lar events. Thirty-two percent of the subjects had established therapy for diabetes. It is recommended that the macronutrient
cardiovascular disease at study entry. After a median follow-up of proportions (carbohydrate, protein, and fat) be individualized
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5 years, there was a nonsignificant reduction (6%) in major mac- based on the patient’s eating patterns, preferences and goals. Gen-
rovascular event rate in the intensively treated group (HbA1c erally most patients with diabetes consume about 45% of their
6.5%) compared to the standard therapy group (HbA1c 7.3%). calories as carbohydrates; 25% to 35% fats; and 10% to 35%
The Veteran Administration Diabetes Trial (VADT) randomly proteins. Limiting the carbohydrate intake and substituting some
assigned 1791 patients in their 50s and 60s with type 2 diabetes of the calories with monounsaturated fats, such as olive oil, rape-
to standard or intensive glucose control. Ninety-seven percent of seed (canola) oil, or the oils in nuts and avocados, can lower tri-
the subjects were men. The primary outcome was a composite of glycerides and increase HDL cholesterol. A Mediterranean-style
myocardial infarction, death from cardiovascular causes, conges- eating pattern (a diet supplemented with walnuts, almonds, hazel
tive heart failure, vascular surgery, inoperable coronary artery dis- nuts, and olive oil) has been shown to improve glycemic control
ease, and amputation for gangrene. All patients had optimized and lower combined endpoints for cardiovascular events and

stroke. Caloric restriction and weight loss is an important goal for Since you have to have 50 g of available carbohydrate to measure
the obese patient with type 2 diabetes. the glycemic index, you cannot assign glycemic indices to foods
Patients with type 1 diabetes or type 2 diabetes on insulin which have very little carbohydrate. Even though it may not be
should be taught carbohydrate counting, so they can administer possible to accurately predict the impact of the glycemic index of a
their insulin bolus for each meal based on its carbohydrate particular food in the context of a meal, it is still reasonable to
content. choose foods with low glycemic index.
The current recommendations for saturated fats and dietary
cholesterol intake for people with diabetes are the same as for the C. Sweeteners The nonnutritive sweetener saccharin is
general population. Saturated fats should be limited to less than widely used as a sugar substitute (sweet and low). Aspartame
10% of daily calories and dietary cholesterol intake should be less (NutraSweet) consists of two major amino acids, aspartic acid, and
than 300 mg/d. For those patients with kidney disease, dietary phenylalanine, which combine to produce a nutritive sweetener
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protein should be maintained at the recommended daily allow- 180 times as sweet as sucrose. A major limitation is its heat lability,
ance of 0.8 g/kg/d. Exchange lists for meal planning can be which precludes its use in baking or cooking. Sucralose (Splenda)
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obtained from the American Diabetes Association and its affiliate and acesulfame potassium (Sunett, Sweet One, DiabetiSweet) are
associations or from the American Dietetic Association, 216 W. two other nonnutritive sweeteners that are heat stable and can be
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Jackson Blvd., Chicago, IL 60606 (312-899-0040 or http://www. used in cooking and baking.
eatright.org). Fructose represents a natural sugar substance that is a highly
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effective sweetener. It induces only slight increases in plasma glu-

Special Considerations in Dietary Control cose levels and does not require insulin for its utilization. How-
ever, because of potential adverse effects of large amounts of
A. Dietary fiber Plant components such as cellulose, gum,
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fructose (up to 20% of total calories) on raising serum cholesterol,

and pectin are indigestible by humans and are termed dietary
triglycerides, and LDL cholesterol, it does not have any advantage
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fiber. Insoluble fibers such as cellulose or hemicellulose increase

as a sweetening agent in the diabetic diet. This does not preclude,
stool bulk and decrease transit time. Soluble fibers such as gums
however, ingestion of fructose-containing fruits and vegetables or
and pectins, found in beans, oatmeal, or apple skin, can delay
fructose-sweetened foods in moderation.
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glucose absorption and so diminish postprandial hyperglycemia.

Sugar alcohols, also known as polyols or polyalcohol, are com-
Although the ADA diet does not require insoluble fiber supple-
monly used as sweeteners and bulking agents. They occur natu-
ments such as added bran, it recommends foods such as oatmeal,
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rally in a variety of fruits and vegetables but are also commercially

cereals, and beans with relatively high soluble fiber content as
made from sucrose, glucose, and starch. Examples are sorbitol,
stable components of the diet in patients with diabetes. High
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xylitol, mannitol, lactitol, isomalt, maltitol, and hydrogenated

soluble fiber content in the diet may also have a favorable effect
starch hydrolysates (HSH). They are not as easily absorbed as
on blood cholesterol levels.
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sugar, so they do not raise blood glucose levels as much as conven-

tional sugars. Therefore, sugar alcohols are often used in food
B. Glycemic index Quantitation of the relative glycemic con-
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products that are labeled as sugar free, such as chewing gum, loz-
tribution of different carbohydrate foods has formed the basis of a enges, hard candy, and sugar-free ice cream. However, if con-
glycemic index in which the area of blood glucose (plotted on a sumed in large quantities, they will raise blood glucose and can
graph) generated over a 3-hour period following ingestion of a test
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also cause bloating and diarrhea.

food containing 50 g of carbohydrate is compared with the area
up
plotted after giving a similar quantity of reference food such as D. Fish oils and other oils Omega-3 fatty acids in high
glucose or white bread: doses have been shown to lower plasma triglycerides and VLDL
cholesterol. They may also reduce platelet aggregation. In the
lic
Blood glucose area of test food Lyon Diet Heart Study in nondiabetic patients, a high intake of
× 100
Blood glucose area of reference food α-linolenic acid was beneficial in secondary prevention of coro-
nary heart disease. This diet, which is rich in vegetables and fruits,
at
White bread is preferred to glucose as a reference standard also supplies a high intake of natural antioxidants. There is limited
because it is more palatable and has less tendency to slow gastric clinical information on the use of these oils in patients with
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emptying by high tonicity, as happens when glucose solution is diabetes.

used. Eating foods with low glycemic index will result in lower
glucose levels after meals. Low glycemic index foods have values of
55 or less and include many fruits (apples, oranges) and vegetables, AGENTS FOR THE TREATMENT OF
grainy breads, pasta, legumes, milk, and yoghurt. High glycemic HYPERGLYCEMIA
index foods have values of 70 and over and include baked potato,
white bread, and most white rice. Glycemic index is lowered by the The drugs for treating type 2 diabetes (Table 17–12), other than
presence of fats and protein when the food is consumed in a mixed insulin, fall into several categories. (1) Drugs that act on the sulfo-
meal. Cooking methods can also affect the glycemic index—thus nylurea receptor complex of the a cell. Sulfonylureas remain
mashed potatoes have a higher glycemic index than baked potato. the most widely prescribed drugs for treating hyperglycemia.

TABLE 17–12 Drugs for treatment of type 2 diabetes.

Duration of
Drug Tablet Size Daily Dose Action (h)
Sulfonylureas
Acetohexamide (Dymelor) 250 and 500 mg 0.25-1.5 g as single dose or in two divided doses 8-24
Chlorpropamide (Diabinese) 100 and 250 mg 0.1-0.5 g as a single dose 24-72
Gliclazide (not available in 80 mg 40-80 mg as single dose; 160-320 mg as divided dose 12
United States)
Glimepiride (Amaryl) 1, 2, and 4 mg 1-4 mg as single dose. 8 mg once a day is maximal dose Up to 24
Glipizide
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(Glucotrol) 5 and 10 mg 2.5-40 mg as single dose or in two divided doses on an 6-12

empty stomach
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(Glucotrol XL) 2.5, 5, and 10 mg Up to 20 mg daily as a single dose Up to 24

Glyburide
(DiaBeta, Micronase) 1.25, 2.5, and 5 mg 1.25-20 mg as single dose or in two divided doses Up to 24
Glynase 1.5, 3, and 6 mg 1.5-19 mg as a single dose or in two divided doses Up to 24
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Tolazamide (Tolinase) 100, 250, and 500 mg 0.1-1 g as single dose or in two divided doses Up to 24
Tolbutamide (Orinase) 250 and 500 mg 0.5-2 g in two or three divided doses 6-12
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Meglitinide Analogs
Repaglinide (Prandin) 0.5, 1, and 2 mg 0.5 to 4 mg three times a day before meals 3
Mitiglinide (available in Japan) 5 and 10 mg 5 or 10 mg three times a day before meals 2
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d-Phenylalanine
Nateglinide (Starlix) 60 and 120 mg 60 or 120 mg three times a day before meals 1.5
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Biguanides
Metformin (Glucophage) 500, 850, and 1000 mg 1-2.5 g; one tablet with meals two or thee times daily 7-12
Extended-release metformin 500 and 750 mg 500-2000 mg once a day Up to 24
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(Glucophage XR)
Thiazolidinediones
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Pioglitazone (Actos) 15, 30, and 45 mg 15-45 mg daily Up to 24

Rosiglitazone (Avandia) 2, 4, and 8 mg 4-8 mg daily (can be divided) Up to 24
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`-Glucosidase Inhibitors
Acarbose (Precose) 50 and 100 mg 75-300 mg in three divided doses with first bite of food 4
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Miglitol (Glyset) 25, 50, and 100 mg 75-300 mg in three divided doses with first bite of food 4
GLP-1 Receptor Agonists
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Albiglutide (Tanzeum) 30, 50 mg single dose Mix with diluent and inject subcutaneously. 30 mg is usual 1 week
pen (powder) dose. Can increase dose to 50 mg if necessary
Dulaglutide (Trulicity) 0.75, 1.5 mg single dose 0.75 mg subcutaneously. Dose can be increased to 1.5 mg if 1 week
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pen or prefilled necessary

syringe
Exenatide (Byetta) 5 and 10 μg 5 μg by subcutaneous injection within 1 hour of breakfast and 6
up
dinner. Increase to 10 μg twice a day after about a month

Do not use if calculated creatinine clearance is <30 mL/min
Exenatide long-acting release 2 mg powder Suspend in provided diluent and inject subcutaneously 1 week
(Bydureon, Byetta LAR)
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Liraglutide (Victoza) 0.6, 1.2, and 1.8 mg 0.6 mg by subcutaneous injection once a day starting dose. 24
Increase to 1.2 mg after a week if no adverse reactions. Dose
can be further increased to 1.8 mg if necessary
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Lixisenatide (Adlyxin) 10 and 10 μg 10 μg by subcutaneous injection daily 24

Increase to 20 μg after two weeks
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DPP-4 Inhibitors
Alogliptin (Nesina) 6.25, 12.5, and 25 mg 25 mg once daily; dose is 12.5 mg daily if calculated creatinine 24
clearance is 30–59 mL/min and 6.25 mg daily if clearance
<30 mL/min
Linagliptin (Tradjenta) 5 mg 5 mg daily 24
Saxagliptin 2.5 and 5 mg 2.5 or 5 mg once a day. Use 2.5 mg dose if calculated creatinine 24
clearance is ≤50 mL/min or if also taking strong CYP 3A4/5
inhibitors like ketoconazole
Sitagliptin 25, 50, and 100 mg 100 mg orally once a day. Reduce dose to 50 mg if calculated 24
creatinine clearance is 30-50 mL/min. Give 25 mg daily if cre-
atinine clearance <30 mL/min
(Continued)

TABLE 17–12 Drugs for treatment of type 2 diabetes. (Continued)

Duration of
Drug Tablet Size Daily Dose Action (h)
Vildagliptin (not available in 50 mg 50 mg once or twice a day. Contraindicated in patients with 24

United States) calculated creatinine clearance ≤60 mL/min or AST/ALT three
times upper limit of normal
SGLT2 Inhibitors
Canagliflozin (Invokana) 100 and 300 mg 100 mg daily is usual dose. Do not use if eGFR 24
<45 mL/min/1.72 m2
300 mg dose can be used if normal eGFR
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Dapagliflozin (Farxiga) 5 and 10 mg 10 mg daily. Use 5 mg dose in hepatic failure 24

Empagliflozin (Jardiance) 10 and 25 mg 10 mg daily. 25 mg can be used if necessary 24
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Others
Bromocriptine (Cycloset) 0.8 mg 0.8 mg daily. Increase weekly by 1 tablet until maximal 24
tolerated dose of 1.6-4.8 mg daily
Colesevelam (Welchol) 625 mg 3 tablets twice a day 24
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Pramlintide 5-mL vial containing For insulin-treated type 2 patients, start at 60-μg dose three 2
0.6 mg/mL times a day (10 U on U100 insulin syringe) and increase to
120 μg three times a day (20 U) if patient has no nausea for
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3-7 days. Give immediately before meal. For type 1 patients,

start at 15 μg three times a day (2.5 U on U100 insulin
syringe) and increase by increments of 15 μg to a maximum
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of 60 μg three times a day as tolerated. Lower insulin dose

by 50% on initiation of therapy to avoid hypoglycemia
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The meglitinide analog repaglinide and the d-phenylalanine In β cells, the ATP-sensitive channels contain four copies each
y
derivative nateglinide also bind the sulfonylurea receptor and of two subunits, the regulatory subunit SUR1, which binds ATP,
stimulate insulin secretion. (2) Drugs that principally lower ADP, and sulfonylureas, and the potassium channel subunit
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glucose levels by their actions on liver, skeletal muscle, or adi- Kir6.2. KATP channels composed of the same subunits are found
pose tissue. Metformin works primarily in the liver. The peroxi- in α cells, GLP-1 secreting intestinal l-cells, and the brain. The
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some proliferator-activated receptor agonists (PPARs), SUR1/Kir6.2 complexes are opened by diazoxide and closed by
rosiglitazone, and pioglitazone appear to have their main effects sulfonylureas at low concentrations (IC50 about 1 nM for gly-
on skeletal muscle and adipose tissue. (3) Drugs that principally buride). Inactivating mutations in SUR1 or Kir6.2 cause persis-
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affect absorption of glucose. The α-glucosidase inhibitors acar- tent depolarization of the β cells and have been identified in
bose and miglitol are currently available drugs in this class. (4)
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patients with hyperinsulinemic hypoglycemia of infancy (see

Drugs that mimic incretin effects or prolong incretin action. Chapter 18). Activating mutations in SUR1 or Kir6.2 prevent
The GLP-1 receptor agonists and the DPP-4 inhibitors fall into depolarization of the β cells and have been identified in patients
this category. (5) Drugs that inhibit reabsorption of filtered
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with neonatal diabetes (see section on Neonatal Diabetes earlier).

glucose in the kidney. The sodium-glucose cotransporter inhibi- KATP channels with different subunit combinations are found
up
tors are such agents. (6) Other drugs. Pramlintide, lowers glucose in other tissues. The combination of SUR2A/Kir6.2 is found in
by suppressing glucagon and slowing gastric emptying. The cardiac and skeletal muscle, and SUR2B/Kir6.1 in vascular
mechanisms by which bromocriptine and colesevelam lower glu- smooth muscle. Channel configurations containing SUR2 sub-
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cose levels have not been defined. units are insensitive to diazoxide but sensitive to other potassium
channel agonists such as pinacidil and cromakalim. Certain chan-
nel closers have much higher affinity for SUR1-containing chan-
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1. DRUGS THAT ACT ON THE nels than SUR2-containing channels (the sulfonylureas
SULFONYLUREA RECEPTOR COMPLEX tolbutamide and gliclazide and the meglitinides nateglinide and
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mitiglinide), while others have similar affinities for both of them

Sulfonylureas (glyburide, glimepiride, and repaglinide). It remains uncertain
The sulfonylureas contain a sulfonic acid-urea nucleus that can whether the different affinities of these drugs for the two classes of
be modified by chemical substitutions to produce agents that receptors have clinical relevance.
have similar qualitative actions but differ widely in potency. Sulfonylureas are not indicated for use in type 1 diabetes
They bind the ATP-sensitive potassium channels (KATP) on the patients since these drugs require functioning pancreatic β cells to
surface of pancreatic β cells, resulting in closure of the channel produce their effect on blood glucose. These drugs are used in
and depolarization of the β cell. This depolarized state permits patients with type 2 diabetes, in whom acute administration
calcium to enter the cell and actively promote insulin release improves the early phase of insulin release that is refractory to
(see Figure 17–5). acute glucose stimulation. Sulfonylureas are metabolized by the

liver and apart from acetohexamide, whose metabolite is more becomes sequestered within the β cell. This may also con-
active than the parent compound, the metabolites of all the other tribute to its prolonged biologic effect despite its relatively
sulfonylureas are weakly active or inactive. The metabolites are short circulating half-life.
excreted by the kidney and, in the case of the second-generation A formulation of micronized glyburide, which apparently
sulfonylureas, partly excreted in the bile. Sulfonylureas are gener- increases its bioavailability, is available in easy to divide tab-
ally contraindicated in patients with severe liver or kidney impair- let sizes of 1.5, 3, and 6 mg.
ment. Idiosyncratic reactions are rare, with skin rashes or Glyburide has few adverse effects other than its potential
for causing hypoglycemia. It should not be used in patients
hematologic toxicity (leukopenia, thrombocytopenia) occurring with liver failure and renal failure because of the risk of
in less than 0.1% of users. hypoglycemia. Elderly patients are at particular risk of hypo-
glycemia even with relatively small daily doses. Glyburide
A. First-generation sulfonylureas (tolbutamide, tolaza- does not cause water retention, as chlorpropamide does, and
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mide, acetohexamide, and chlorpropamide) Tolbuta- even slightly enhances free water clearance.
mide is supplied in tablets of 500 mg. It is rapidly oxidized in the b. Glipizide (glydiazinamide)—Glipizide is supplied in tab-
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liver to an inactive form. Because its duration of effect is short lets containing 5 and 10 mg. For maximum effect in reduc-
(6-10 hours), it is usually administered in divided doses (eg, 500 mg ing postprandial hyperglycemia, this agent should be
ingested 30 minutes before breakfast, because rapid absorp-
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before each meal and at bedtime). The usual daily dose is 1.5
tion is delayed when the drug is taken with food. The rec-
to 3 g; some patients, however, require only 250 to 500 mg daily. ommended starting dose is 5 mg daily but 2.5-mg dose may
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Acute toxic reactions such as skin rashes are rare. Because of its be sufficient in elderly patients with early diabetes. The dose
short duration of action, which is independent of renal function, can gradually be increased by 2.5 or 5-mg increments.
tolbutamide is probably the safest agent to use in elderly patients, Although as much as 15 mg can be given as a single daily
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in whom hypoglycemia would be a particularly serious risk. Pro- dose before breakfast, most patients do better with divided
longed hypoglycemia has been reported rarely, mainly in patients dosing, taking 5 mg before each meal or taking 10 mg
before breakfast and before dinner. The maximum recom-
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receiving certain drugs (eg, warfarin, phenylbutazone, or sulfon-

mended dose is 40 mg/d, although doses above 20 mg prob-
amides) that compete with sulfonylureas for hepatic oxidation, ably provide little additional benefit in poor responders. At
resulting in maintenance of high levels of unmetabolized active least 90% of glipizide is metabolized in the liver to inactive
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sulfonylureas in the circulation. products, and only a small fraction is excreted unchanged in
Tolazamide, acetohexamide, and chlorpropamide are rarely the urine. Glipizide therapy is contraindicated in patients
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used. Chlorpropamide has a prolonged biologic effect, and severe with liver failure. Because of its lower potency and shorter
half-life, it is preferable to glyburide in elderly patients and
hypoglycemia can occur especially in the elderly, because their for those patients with renal impairment.
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renal clearance declines with aging. Its other side effects include
Glipizide is also available as a slow-release preparation
alcohol-induced flushing and hyponatremia due to its effect on (Glucotrol-XL, 2.5, 5, and 10-mg tablets). The medication
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vasopressin secretion and action. is enclosed in a nonabsorbable shell that contains an osmotic
compartment that expands slowly, thereby slowly pumping
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Second-generation sulfonylureas (glyburide, glipizide, out the glipizide in a sustained manner. It provides extended
gliclazide, and glimepiride) These agents have similar chemi- release during transit through the gastrointestinal tract, with
cal structures, with cyclic carbon rings at each end of the sulfonyl- greater effectiveness in lowering of prebreakfast hyperglyce-
mia than the shorter duration, immediate-release standard
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urea nucleus; this causes them to be highly potent (100- to 200-fold

more potent than tolbutamide). The drugs should be used with glipizide tablets. However, this formulation appears to have
sacrificed glipizide’s reduced propensity for severe hypogly-
up
caution in patients with cardiovascular disease as well as in elderly cemia compared with longer acting glyburide without show-
patients, in whom hypoglycemia would be especially dangerous. ing any demonstrable therapeutic advantages over
a. Glyburide (glibenclamide)—Glyburide is supplied in tab- glyburide.
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lets containing 1.25, 2.5, and 5 mg. The usual starting dose c. Gliclazide (not available in the United States)—This drug
is 2.5 mg/d, and the average maintenance dose is 5 to 10 mg/d is another intermediate duration sulfonylurea with a dura-
given as a single morning dose. If patients are going to tion of action of about 12 hours. It is available as 80-mg
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respond to glyburide, they generally do so at doses of 10 mg/d tablets. The recommended starting dose is 40 to 80 mg/d
or less, given once daily. If they fail to respond to 10 mg/d, with a maximum dose of 320 mg. Doses of 160 mg and
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it is uncommon for an increase in dosage to result in above are given as divided doses before breakfast and dinner.
improved glycemic control. Maintenance doses higher than The drug is metabolized by the liver, and the metabolites
20 mg/d are not recommended and may even worsen hyper- and conjugates have no hypoglycemic effect. An extended-
glycemia. Glyburide is metabolized in the liver into products release preparation is also available.
with such low hypoglycemic activity that they are considered d. Glimepiride—This sulfonylurea is supplied in tablets con-
clinically unimportant unless renal excretion is compro- taining 1, 2, and 4 mg. It has a long duration of effect with
mised. Although assays specific for the unmetabolized com- a half-life of 5 hours, allowing once-daily administration.
pound suggest a plasma half-life of only 1 to 2 hours, the Glimepiride achieves blood glucose lowering with the lowest
biologic effects of glyburide clearly persist for 24 hours after dose of any sulfonylurea compound. A single daily dose of
a single morning dose in diabetic patients. Glyburide is 1 mg/d has been shown to be effective, and the maximal
unique among sulfonylureas in that it not only binds to the recommended dose is 8 mg. It is completely metabolized by
pancreatic β cell membrane sulfonylurea receptor but also the liver to relatively inactive metabolic products.

Meglitinide Analogs current recommendation is to start this drug at diagnosis. A side

benefit of metformin therapy is its tendency to improve both fast-
Repaglinide is supplied as 0.5, 1, and 2-mg tablets. Its structure
ing and postprandial hyperglycemia and hypertriglyceridemia in
is similar to that of glyburide but lacks the sulfonic acid-urea moi-
obese patients with diabetes without the weight gain associated
ety. It also acts by binding to the sulfonylurea receptor and closing
with insulin or sulfonylurea therapy. It is dispensed as 500-, 850-,
the ATP-sensitive potassium channel. It is rapidly absorbed from
and 1000-mg tablets. A 500- and 750-mg extended-release prepa-
the intestine and then undergoes complete metabolism in the liver
ration is also available. Eighty-five percent of the maximal glucose-
to inactive biliary products, giving it a plasma half-life of less than
lowering effect is achieved by a daily dose of 1500 mg, and there
1 hour. The drug therefore causes a brief but rapid pulse of insu-
is little benefit from giving more than 2000 mg daily. It is impor-
lin. The starting dose is 0.5 mg three times a day 15 minutes
tant to begin with a low dose and increase the dosage very gradu-
before each meal. The dose can be titrated to a maximum daily
ally in divided doses—taken with meals—to reduce minor
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dose of 16 mg. Hypoglycemia is the main side effect. In clinical

gastrointestinal upsets. A common schedule would be one 500-mg
trials, when the drug was compared with glyburide, a long-acting
tablet three times a day with meals or one 850-mg or 1000-mg
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sulfonylurea, there was a trend toward less hypoglycemia. Like the

tablet twice daily at breakfast and dinner. The maximum recom-
sulfonylureas, it causes weight gain. Metabolism is by the cyto-
mended dose is 850 mg three times a day. Up to 2000 mg of the
chrome P450 3A4 isoenzyme. Other drugs that induce or inhibit
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extended-release preparation can be given once a day.

this isoenzyme may increase or inhibit the metabolism of repa-
The most frequent side effects of metformin are gastrointesti-
glinide. The drug may be useful in patients with renal impairment
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nal symptoms (anorexia, nausea, vomiting, abdominal discomfort,

or in the elderly.
diarrhea), which occur in up to 20% of patients. These effects are
Mitiglinide is a benzylsuccinic acid derivative that is very simi-
dose-related, tend to occur at onset of therapy, and often are tran-
lar to repaglinide in its clinical effects. It binds to the sulfonylurea
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sient. However, in 3% to 5% of patients, therapy may have to be

receptor causing a brief pulse of insulin. It is given as a 5- or
discontinued because of persistent diarrheal discomfort. In a ret-
10-mg dose just before a meal and reduces the postprandial rise in
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rospective analysis, it has been reported that patients who switched

blood glucose. It has been approved for use in Japan.
from immediate-release metformin to a comparable dose of
extended-release metformin experienced fewer gastrointestinal
c-Phenylalanine Derivative
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side effects.
Nateglinide is supplied in tablets of 60 and 120 mg. This drug Absorption of vitamin B12 appears to be reduced during
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binds the sulfonylurea receptor and closes the ATP-sensitive potas- chronic metformin therapy but usually the vitamin B12 levels
sium channel. The drug is rapidly absorbed from the intestine, remain in the normal range. Screening of serum vitamin B12 levels
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reaching peak plasma levels within 1 hour. It is metabolized in the should be considered if the patient develops a macrocytic anemia
liver and has a plasma half-life of about 1.5 hours. Like repa- or if the patient develops peripheral neuropathy symptoms.
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glinide, it causes a brief rapid pulse of insulin, and when given Screening may also be considered in patients who have been on
before a meal, it reduces the postprandial rise in blood glucose. the drug for many years. Increased intake of dietary calcium may
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The 60-mg dose is used in patients with mild elevations in HbA1c. prevent the metformin-induced B12 malabsorption. If pernicious
For most patients, the recommended starting and maintenance anemia is suspected then measurements of methylmalonate,
dosage is 120 mg three times a day before meals. Like the other homocysteine and antibodies to intrinsic factor should be per-
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insulin secretagogues, its main side effects are hypoglycemia and formed. Hypoglycemia does not occur with therapeutic doses of
weight gain. metformin, which permits its description as a euglycemic or anti-
up
hyperglycemic drug rather than an oral hypoglycemic agent. Der-

matologic or hematologic toxicity is rare.
2. DRUGS THAT ACT ON INSULIN Metformin both increases lactate production by uncoupling
lic
TARGET TISSUES mitochondrial oxidative phosphorylation, especially in the gut,

and reduces lactate removal by the liver by blocking gluconeogen-
Metformin esis. At therapeutic doses of metformin, serum lactate levels rise
at
Metformin (1,1-dimethylbiguanide hydrochloride) is used, either only minimally if at all, since other organs such as the kidney can
alone or in conjunction with other oral agents or insulin, in the remove the slight excess. However, if tissue hypoxia occurs, the
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treatment of patients with type 2 diabetes. metformin-treated patient is at higher risk for lactic acidosis due
Metformin acts primarily through AMPK (see Figure 17–8), to compromised lactate removal. Metformin has a half-life of 1.5
which it activates by uncoupling mitochondrial oxidative phos- to 3 hours, does not bind to plasma proteins, and is excreted
phorylation and increasing cellular AMP levels. Metformin’s thera- unchanged by the kidneys. With renal failure, plasma levels of
peutic effects primarily derive from its effects on the liver, where metformin can rise far above the therapeutic range and increase
increased AMPK activity reduces hepatic gluconeogenesis and lactate production and block hepatic uptake sufficiently to pro-
lipogenesis. Metformin is a substrate for organic cation transporter voke lactic acidosis even in the absence of other causes of increased
1, which is abundantly expressed in hepatocytes and in the gut. lactic acid production. Metformin can be safely used in patients
Metformin is the first-line therapy for patients with type 2 with estimated glomerular filtration rate (eGFR) between 45 and
diabetes. It is ineffective in patients with type 1 diabetes. The 60 mL/min/1.73 m2. It can be used cautiously in patients with

eGFR between 30 and 45 mL/min/1.73 m2. It is contraindicated HDL cholesterol (15%) but did not cause a consistent change in
if the eGFR is less than 30 mL/min/1.73 m2. Acute kidney failure total cholesterol and LDL cholesterol levels. A prospective ran-
can occur rarely in certain patients receiving radiocontrast agents. domized comparison of the metabolic effects of pioglitazone and
Metformin therapy should therefore be temporarily halted on the rosiglitazone in patients showed similar effects on HbA1c and
day of radiocontrast administration and restarted a day or two weight gain. Pioglitazone-treated subjects, however, had lower
later after confirmation that renal function has not deteriorated. total cholesterol, LDL cholesterol, and triglyceride levels when
Renal function should be checked at least annually in patients on compared with rosiglitazone. Small prospective studies have also
metformin therapy; and lower doses should be used in the elderly shown that treatment with these drugs leads to improvement of
who may have limited renal reserve and in those with eGFR biochemical and histological features of nonalcoholic fatty liver
between 30 and 45 mL/min/1.73 m2. disease. The thiazolidinediones also may limit vascular smooth
Alcoholics and patients with liver failure should not take met- muscle proliferation after injury and there are reports that piogli-
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formin—lactic acidosis can occur because of impaired hepatic tazone can reduce neointimal proliferation after coronary stent
clearance of lactate. The drug is relatively contraindicated in placement. Also, in one double-blind, placebo-controlled study,
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patients with cardiorespiratory insufficiency, because they have a rosiglitazone was shown to be associated with a decrease in the
propensity to develop hypoxia that would aggravate the lactic acid ratio of urinary albumin to creatinine.
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production already occurring from metformin therapy. Safety concerns and some troublesome side effects have
emerged over this class of drugs that limit their use. A meta-analysis
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of 42 randomized clinical trials with rosiglitazone suggested that

Peroxisome Proliferator–Activated
this drug increases the risk of angina pectoris or myocardial
Receptor Agonists infarction. A meta-analysis of clinical trials with pioglitazone did
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Thiazolidinediones are insulin sensitizers exerting their antidia- not show a similar finding. Although conclusive data are lacking,
betic effects through the activation of PPARγ (see discussion on the European Medicines Agency suspended the use of rosigli-
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PPAR nuclear receptors in insulin action and insulin resistance tazone in Europe. In the United States, the FDA established a
earlier). Observed effects of thiazolidinediones include increased restricted distribution program for rosiglitazone. A subsequent
GLUT expression (GLUT 1 and GLUT 4); decreased free fatty large prospective clinical trial (the RECORD study) failed to con-
y
acid levels; decreased hepatic glucose output; increased adiponec- firm the meta-analysis finding and the restrictions were lifted in
tin and decreased resistin release from adipocytes; and increased the United States.
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differentiation of preadipocytes into adipocytes. They have also Edema occurs in about 3% to 4% of patients receiving mono-
been demonstrated to decrease levels of plasminogen activator therapy with rosiglitazone or pioglitazone. The edema occurs
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inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, more frequently (10%-15%) in patients receiving concomitant
and interleukin-6. Like the biguanides, this class of drugs does not insulin therapy and may result in congestive heart failure. The
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cause hypoglycemia. drugs are contraindicated in diabetic individuals with New York
Rosiglitazone and pioglitazone are available for clinical use. Heart Association class III or IV heart failure. Thiazolidinediones
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Both are effective as monotherapy and in combination with sulfo- have also rarely been reported as being associated with new onset
nylureas, metformin, or insulin. When used as monotherapy, or worsening macular edema which resolved or improved once the
these drugs lower HbA1c by about 1 or 2 percentage points. When drug was discontinued.
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used in combination with insulin, they can result in a 30% to In experimental animals, rosiglitazone stimulates bone marrow
50% reduction in insulin dosage, and some patients can come off adipogenesis at the expense of osteoblastogenesis resulting in a
up
insulin completely. The dosage of rosiglitazone is 4 to 8 mg daily decrease in bone mineral density. An increase in fracture risk in
and of pioglitazone 15 to 45 mg daily, and the drugs do not have women (but not men) has been reported with both rosiglitazone
to be taken with food. Rosiglitazone is primarily metabolized by and pioglitazone. The fracture risk is in the range of 1.9 per 100
lic
the CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP patient years with the thiazolidinedione. In at least one study of
2C8 and CYP 3A4. rosiglitazone, the fracture risk was increased in premenopausal as
The combination of a thiazolidinedione and metformin has well as postmenopausal women. Other side effects include ane-
at
the advantage of not causing hypoglycemia. Patients inadequately mia, which occurs in 4% of patients treated with these drugs; it
managed on sulfonylureas can do well on a combination of sulfo- may be due to a dilutional effect of increased plasma volume
e
nylurea and rosiglitazone or pioglitazone. About 25% of patients rather than a reduction in red cell mass. Weight gain occurs, espe-
in clinical trials fail to respond to these drugs, presumably because cially when the drug is combined with a sulfonylurea or insulin.
they are significantly insulinopenic. Some of the weight gain is fluid retention, but there is also an
In addition to glucose-lowering, the thiazolidinediones have increase in total fat mass. In preclinical studies with pioglitazone,
effects on lipids and other cardiovascular risk factors. Rosigli- bladder tumors were observed in male rats receiving clinically
tazone therapy is associated with increases in total cholesterol, relevant doses of the medication. Initial clinical reports indicated
LDL cholesterol (15%), and HDL cholesterol (10%). There is a that this might also be true in humans. A 10-year observational
reduction in free fatty acids of about 8% to 15%. The changes in cohort study of patients taking pioglitazone, however, failed to
triglycerides were generally not different from placebo. Piogli- find an association with bladder cancer. A large multipopulation
tazone in clinical trials lowered triglycerides (9%) and increased pooled analysis (1.01 million persons over 5.9 million person years)

also failed to find an association between cumulative exposure to particularly with doses >300 mg/d). This generally returns
pioglitazone or rosiglitazone and incidence of bladder cancer. to normal on stopping this drug. In the UKPDS, approxi-
Another population based study generating 689,616 person mately 2000 patients on diet, sulfonylurea, metformin, or
years of follow-up did find that pioglitazone but not rosigli- insulin therapy were randomized to acarbose or placebo
therapy. By 3 years, 60% of the patients had discontinued
tazone was associated with an increased risk of bladder cancer— the drug, mostly because of gastrointestinal symptoms. In
hazard ratio 1.63 for pioglitazone, 95% confidence intervals the 40% of patients who remained on the drug, acarbose
1.22 to 2.19. Troglitazone, the first drug in this class, was with- was associated with a 0.5% lowering of HbA1c compared
drawn from clinical use because of drug-associated fatal liver with placebo.
failure. The two currently available agents, rosiglitazone and b. Miglitol is similar to acarbose in terms of its clinical effects.
pioglitazone, have thus far not caused hepatotoxicity. The FDA It is indicated for use in diet- or sulfonylurea-treated
has, however, recommended that patients should not initiate patients with type 2 diabetes. Therapy is initiated at the low-
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drug therapy if there is clinical evidence of active liver disease or est effective dosage of 25 mg three times a day. The usual
maintenance dose is 50 mg three times a day, although some
pretreatment elevation of the alanine aminotransferase (ALT)
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patients may benefit from increasing the dose to 100 mg

level that is 2.5 times greater than the upper limit of normal. three times a day. Gastrointestinal side effects occur as with
Obviously, caution should be used in initiation of therapy in acarbose. The drug is not metabolized and is excreted
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patients with even mild ALT elevations. Liver biochemical tests unchanged by the kidney. Theoretically, absorbable
should be performed prior to initiation of treatment and peri- α-glucosidase inhibitors could induce a deficiency of one or
more of α-glucosidases involved in cellular glycogen metab-
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odically thereafter.
olism and biosynthesis of glycoproteins. This does not occur
in practice because—unlike the intestinal mucosa, which is
3. DRUGS THAT AFFECT GLUCOSE exposed to a high concentration of the drug—circulating
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plasma levels are 200-fold to 1000-fold lower than those

ABSORPTION needed to inhibit intracellular α glucosidases. Miglitol
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should not be used in renal failure because its clearance is

Alpha-Glucosidase Inhibitors impaired in this setting.
Drugs of this family are competitive inhibitors of intestinal brush
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border α glucosidases. Two of these drugs, acarbose and miglitol, 4. INCRETINS

are available for clinical use in the United States. Voglibose,
The gut makes several incretins, gut hormones that amplify post-
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another α glucosidase inhibitor, is available in Japan, Korea, and

India. Acarbose and miglitol are potent inhibitors of glucoamy- prandial insulin secretion, including glucagon-like peptide-1
(GLP-1, see Figure 17–9) and glucose-dependent insulinotropic
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lase, α-amylase, and sucrase. They are less effective on isomaltase

and are ineffective on trehalase or lactase. Acarbose binds 1000 polypeptide (GIP). Therapeutic drugs in this class include GLP-1
times more avidly to the intestinal disaccharidases than do prod- receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibi-
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ucts of carbohydrate digestion or sucrose. A fundamental differ- tors, which increase levels of both GLP-1 and GIP.
When GLP-1 is infused in patients with type 2 diabetes, it
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ence exists between acarbose and miglitol in their absorption.

Acarbose has the molecular mass and structural features of a tetra- stimulates insulin secretion and lowers glucose levels. GLP-1,
saccharide, and very little (~2%) crosses the microvillar mem- unlike the sulfonylureas, has only a modest insulin stimulatory
effect under normoglycemic conditions. This means that GLP-1
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brane. Miglitol, however, is structurally similar to glucose and is

absorbable. Both drugs delay the absorption of carbohydrates and administration has a lower risk of causing hypoglycemia than the
sulfonylureas. GLP-1, in addition to its insulin stimulatory effect,
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reduce postprandial glycemic excursion.

a. Acarbose is available as 50- and 100-mg tablets. The recom- also has a number of other pancreatic and extrapancreatic effects
mended starting dose is 50 mg twice daily, gradually increas- (see Table 17–4).
ing to 100 mg three times daily. For maximal benefit on
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postprandial hyperglycemia, acarbose should be given with GLP-1 Receptor Agonists

the first mouthful of food ingested. In diabetic patients it
reduces postprandial hyperglycemia by 30% to 50%, and its GLP-1 is rapidly proteolyzed by DPP-4 and by other enzymes
at
overall effect is to lower the HbA1c by 0.5% to 1%. The such as endopeptidase 24.11. It is also cleared rapidly by the kid-
principal adverse effect, seen in 20% to 30% of patients, is ney. As a result, the half-life of GLP-1 is only 1 to 2 minutes. The
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flatulence. This is caused by undigested carbohydrate reach- native peptide, therefore, cannot be used therapeutically. Instead,
ing the lower bowel, where gases are produced by bacterial the approach taken has been to develop metabolically stable ana-
flora. In 3% of cases, troublesome diarrhea occurs. This
gastrointestinal discomfort tends to discourage excessive logs or derivatives of GLP-1 that are not subject to the same
carbohydrate consumption and promotes improved compli- enzymatic degradation or renal clearance. Five GLP-1 receptor
ance of patients with type 2 diabetes with their diet agonists, exenatide, liraglutide, albiglutide, dulaglutide, and lixisena-
prescriptions. tide are available for clinical use.
When acarbose is given alone, there is no risk of hypogly- a. Exenatide (exendin 4) is a GLP-1 receptor agonist isolated
cemia. However, if combined with insulin or sulfonylureas, from the saliva of the Gila monster (a venomous lizard) that
it may increase risk of hypoglycemia from these agents. A is resistant to DPP-4 action and is cleared by the kidney. Its
slight rise in hepatic aminotransferases has been noted in half life is 2.4 hours and its glucose lowering effect is about
clinical trials (5% vs 2% in placebo controls, and 6 hours. Exenatide is dispensed as two fixed-dose pens

(5 and 10 μg). It is injected within the hour before breakfast injection. The maximum recommended dose is 1.5 mg
and before dinner. Patients should be prescribed the 5-μg weekly. Dulaglutide monotherapy and combination therapy
pen for the first month and then, if tolerated, the dose lowers HbA1c by about 0.7% to 1.6%. Weight loss ranges
should be increased to 10 μg twice daily. The drug is not from 2 pounds to 7 pounds.
recommended in patients with glomerular filtration rate less
than 30 mL/min. ixisenatide is a modified exendin 5 (deletion of c-terminal
e. L
In clinical trials, adding exenatide to the therapeutic regi- proline and addition of 6 lysines) with high affinity for the
men of patients with type 2 diabetes who are already taking GLP-1 receptor. Its half-life is about 2 to 4 hours. Dosing is
metformin or a sulfonylurea (or both) further lowered the initiated at 10 mg daily and increased to 20 mg daily after
HbA1c value by 0.4% to 0.6% over a 30-week period. These two weeks. Lixisenatide monotherapy and combination
patients also lost 3 to 6 lb in weight. In an open-label exten- therapy lowers HbA1c by about 0.7%.
sion study up to 80 weeks, the HbA1c reduction was sus-
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tained, and there was further weight loss (to a total loss of The most frequent adverse reactions of the GLP-1 receptor
~10 lb). Exenatide LAR is a once weekly preparation that is agonists are nausea (11%-40%), vomiting (4%-13%), and diar-
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dispensed as a powder (2 mg). It is suspended in the pro-

vided diluent just prior to injection. In comparative clinical rhea (9%-17%). The reactions are more frequent at the higher
trials, the long-acting drug lowers the HbA1c level a little doses. Albiglutide tends to have the lowest rates of these reactions.
In clinical trials about 1% to 5% of participants withdrew from
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more than the twice daily drug. Low-titer antibodies against

exenatide develop in over one-third (38%) of patients, but the studies because of the gastrointestinal symptoms.
the clinical effects are not attenuated. High-titer antibodies All the GLP-1 receptor agonists are associated with increased risk
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develop in a subset of patients (~6%), and in about half of pancreatitis. The FDA reported 30 postmarketing reports of
of these cases, an attenuation of glycemic response has acute pancreatitis in patients taking exenatide. The pancreatitis was
been seen.
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severe (hemorrhagic or necrotizing) in 6 instances, and 2 of these

b. L iraglutide is a soluble fatty acid acylated GLP-1 analog— patients died. In the liraglutide, albiglutide, and dulaglutide clinical
with replacement of lysine with arginine at position 34 and
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trials, there were 13, 6, and 5 cases of pancreatitis in the drug-

the attachment of a C16 acyl chain to a lysine at position treated groups versus 1, 2, and 1 case(s) in the comparator groups,
26. The fatty-acyl GLP-1 retains affinity for GLP-1 recep- respectively. This translates to about 1.4-2.2 versus 0.6-0.9 cases of
tors, but the addition of the C16 acyl chain allows for non-
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pancreatitis per 1000 patient years. Patients taking GLP-1 receptor

covalent binding to albumin, both hindering DPP-4 access agonists should be advised to seek immediate medical care if they
to the molecule and contributing to a prolonged half-life
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experience unexplained persistent severe abdominal pain.

and duration of action. The half-life is approximately 12 hours The FDA also reported 16 cases of kidney impairment and 62
allowing the drug to be injected once a day. The dosing is
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cases of acute kidney injury taking exenatide. Some of these patients

initiated at 0.6 mg daily, increased after 1 week to 1.2 mg had preexisting kidney disease, and others had one or more risk fac-
daily. Some patients may benefit from increasing the dose to tors for kidney disease. A number of the patients reported nausea,
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1.8 mg. In clinical trials lasting 26 and 52 weeks, adding vomiting, and diarrhea, and it is possible that these side effects
liraglutide to the therapeutic regimen (metformin, sulfonyl-
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caused volume depletion and contributed to the development of

urea, thiazolidinedione) of patients with type 2 diabetes renal injury. For this reason, the GLP-1 receptors agonists should be
further lowered the HbA1c value. Depending on the dose prescribed cautiously in patients with kidney impairment.
and design of the study, the HbA1c decline was in the range
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GLP-1 receptor agonists stimulate C-cell neoplasia and cause

of 0.6% to 1.5%. The patients had sustained weight loss of medullary thyroid carcinoma in rats. Human C-cells express very
1 to 6 lb. Liraglutide at a dose of 3 mg daily has been
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few GLP-1-receptors, and the relevance to human therapy is

approved for weight loss. unclear. The medications, however, should not be used in patients
c. Albiglutide is a human GLP-1 dimer fused to human albu- with personal or family history of medullary thyroid carcinoma or
min. It is rendered resistant to DPP-4 action by a glycine
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multiple endocrine neoplasia (MEN) syndrome type 2.

substitution for alanine at position 8. The half-life of albiglu-
tide is about 5 days and a steady state is reached after 4-5
DPP-4 Inhibitors
at
weeks of once weekly administration. The usual dose is 30 mg

weekly by subcutaneous injection. The dose can be increased An alternative to the use of GLP-1 receptor agonists involves inhi-
e
to 50 mg weekly, if necessary. The pen contains a lyophilized bition of the enzyme DPP-4 with prolongation of the action of
powder that is reconstituted just prior to administration. Albi- endogenously released GLP-1 and GIP. Four oral DPP-4 inhibi-
glutide monotherapy and combination therapy lowers HbA1c tors, sitagliptin, saxagliptin, linagliptin, and alogliptin are avail-
by about 0.8%. Weight loss is much less than with exenatide able for the treatment of type 2 diabetes in the United States. An
and liraglutide. additional DPP-4 inhibitor, vildagliptin, is available in Europe.
d. Dulaglutide consists of two GLP-1 analog molecules cova-
lently linked to an Fc fragment of human IgG4. The GLP-1 a. Sitagliptin when used alone or in combination with other
diabetes medicines additionally lowers HbA1c by approxi-
molecule is 90% homologous to native human GLP-1. The mately 0.5%. The usual dose of sitagliptin is 100 mg once
amino acid substitutions improve solubility and resist daily, but the dose is reduced to 50 mg daily if the calculated
DPP-4 action. The half-life of dulaglutide is about 5 days. creatinine clearance is 30 to 50 mL/min and to 25 mg for
The usual dose is 0.75 mg weekly by subcutaneous clearances less than 30 mL/min. Unlike exenatide, sitagliptin

does not cause nausea or vomiting. It also does not result in nasopharyngitis and hypersensitivity reactions (urticaria,
weight loss. The main adverse effect appears to be a predis- angioedema, localized skin exfoliation, bronchial hyperreac-
position to nasopharyngitis or upper respiratory tract infec- tivity). In one study, there were eight cases of pancreatitis in
tion. A small increase in neutrophil count of approximately 4687 patients exposed to drug (4311 patient years) with 0
200 cells/mL has also occurred. Since its FDA approval and cases in 1183 patients receiving placebo (433 patient years).
clinical use, there have been reports of serious allergic reac- ildagliptin, like the other DPP-4 inhibitors, lowers HbA1c
e. V
tions to sitagliptin, including anaphylaxis, angioedema, and by about 0.5% to 1% when added to the therapeutic regi-
exfoliative skin conditions, including Stevens-Johnson syn- men of patients with type 2 diabetes. The dose is 50 mg once
drome. There have also been reports of pancreatitis (88 cases
including two cases of hemorrhagic or necrotizing pancreati- or twice a day. The adverse reactions include upper respira-
tis). The frequency of these events is unclear. DPP-4 is a tory tract infections, nasopharyngitis, dizziness, and head-
pleiotropic enzyme that inactivates a variety of peptide hor- ache. Rare cases of hepatic dysfunction including hepatitis
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mones, neuropeptides, and chemokines and DPP-4 inhibi- have been reported. Liver function testing is recommended,
tors have been shown to prolong the action of neuropeptide quarterly the first year, and periodically thereafter.
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Y and substance P. Whether its inhibition over a long-term

period will have negative consequences is not known. Animal studies using much higher doses of DPP-4 inhibitors and
b. Saxagliptin when added to the therapeutic regimen (metfor- GLP-1-receptor agonists than are used in humans caused expansion
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min, sulfonylurea, thiazolidinedione) of patients with of pancreatic ductal glands and generation of premalignant pancre-
type 2 diabetes further lowered the HbA1c value by about atic intraepithelial (PanIN) lesions that have the potential to progress
to pancreatic adenocarcinoma. There is, however, currently no evi-
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0.7% to 0.9%. The dose is 2.5 or 5 mg once a day. The

2.5-mg dose should be used in patients with calculated cre- dence that these drugs cause pancreatic cancer in humans.
atinine clearance less than 50 mL/min. The drug is weight
5. SODIUM-GLUCOSE COTRANSPORTER
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neutral. The main adverse reactions were upper respiratory

tract infection, naspharyngitis, headache, and urinary tract 2 INHIBITORS
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infection. There is also small reversible dose-dependent Glucose is freely filtered by the renal glomeruli and is reabsorbed
reduction in absolute lymphocyte count which remains in the proximal tubules by the action of sodium-glucose cotrans-
within normal limits. Hypersensitivity reactions such as urti- porters (SGLT). Sodium-glucose cotransporter 2 (SGLT2)
y
caria and facial edema occurred in 1.5% of patients on the accounts for about 90% of glucose reabsorption and its inhibition
drug compared to 0.4% with placebo. The metabolism of causes glycosuria in people with diabetes, lowering plasma glucose
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saxagliptin is through CYP 3A4/5; so strong inhibitors or levels. The SGLT2 inhibitors canagliflozin, dapagliflozin, and
inducers of CYP 3A4/5 will affect the pharmacokinetics of empagliflozin are approved for clinical use in the United States.
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saxagliptin and its active metabolite. Saxagliptin may increase

the risk of heart failure. In a postmarketing study of 16,492 a. Canagliflozin reduces the threshold for glycosuria from a
plasma glucose threshold of ~180 mg/dL to 70–90 mg/dL.
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type 2 diabetes patients, there were 289 cases of heart failure It has been shown to reduce HbA1c by 0.6% to 1% when
in the saxagliptin group (3.5%) and 228 cases in the placebo used alone or in combination with other oral agents or insu-
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group (2.8%)—a hazard ratio of 1.27. Patients at the highest lin. It also results in modest weight loss of 2–5 kg. The usual
risk for failure were those who had a history of heart failure, dose is 100 mg daily but up to 300 mg daily can be used in
had elevated levels of plasma N-terminal pro-brain natri- patients with normal kidney function.
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uretic peptide (NT-pBNP) or had renal impairment. b. Dapagliflozin is an SGLT2 inhibitor that has been shown
c. Alogliptin lowers HbA1c by about 0.5% to 0.6% when to reduce HbA1c levels by 0.5% to 0.8% when used alone or
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added to metformin, sulfonylurea, or pioglitazone. The usual in combination with other oral agents or insulin. It also
results in modest weight loss of about 2 to 4 kg. The usual
dose is 25 mg orally daily. The 12.5-mg dose is used in patients
dose is 10 mg daily but 5 mg daily is the recommended
with calculated creatinine clearance of 30 to 60 mL/min, initial dose in patients with hepatic failure.
lic
and 6.25 mg for clearance less than 30 mL/min. In clinical c. Empagliflozin reduces HbA1c by 0.5% to 0.7% when used
trials, pancreatitis occurred in 11 of 5902 patients on alo- alone or in combination with other oral agents or insulin. It
gliptin (0.2%) and in 5 of 5183 patients receiving all com- also results in modest weight loss of about 2 to 3 kg. The
at
parators (<0.1%). There have been reports of hypersensitivity usual dosage is 10 mg daily but a higher dose of 25 mg daily
reactions (anaphylaxis, angioedema, Stevens-Johnson syn- can be used. In a postmarketing multinational study of 7020
e
drome). Cases of hepatic failure have been reported but it is type 2 patients with known cardiovascular disease, the addi-
unclear if alogliptin was the cause. The medication, however, tion of empagliflozin was associated with a lower primary
composite outcome of death from cardiovascular causes,
should be discontinued in the event of liver failure. nonfatal myocardial infarction, or non-fatal stroke (hazard
In a large postmarketing study, alogliptin, like saxagliptin, ratio 0.86, p = 0.04). The mechanism(s) regarding the ben-
was associated with a slightly increased rate of heart failure. efit remains unclear. Weight loss, lower blood pressure, and
d. L inagliptin lowers HbA1c by about 0.4% to 0.6% when diuresis may have played a role since there were fewer deaths
added to metformin, sulfonylurea, or pioglitazone. The dose from heart failure in the treated group whereas the rates of
is 5 mg orally daily, and since it is primarily excreted unme- myocardial infarction were unaltered. Additional studies
tabolized through the bile, no dose adjustment is needed in with empagliflozin and other SGLT2 inhibitors are needed
patients with renal failure. The adverse reactions include to confirm this result.

As might be expected, the efficacy of the SGLT2 inhibitors is diabetes, the initiation dose is 60 μg premeals increased to
reduced in chronic kidney disease. They can also increase creatinine 120 μg in 3 to 7 days if no significant nausea occurs.
and decrease eGFR, especially in patients with kidney impairment. b. Bromocriptine, a dopamine 2 receptor agonist, has been
Canagliflozin is contraindicated in patients with eGFR less than shown to modestly lower HbA1c by 0.1% to 0.5% when
45 mL/min/1.73 m2. The main side effects are increased incidence compared to baseline and 0.4% to 0.5% compared to pla-
cebo. The tablet dose is 0.8 mg and the daily dose is 2 (1.6 g)
of genital mycotic infections and urinary tract infections affecting to 6 (4.8 mg) tablets as tolerated. Common side effects are
~8% to 9% of patients. There have also been reports of cases of nausea, vomiting, dizziness, and headache.
pyelonephritis and septicemia requiring hospitalization. The glycos- c. Colesevelam, the bile acid sequestrant, when added to met-
uria can cause intravascular volume contraction and hypotension. formin or sulfonylurea or insulin lowered HbA1c 0.3% to
Canagliflozin has been reported to cause a decrease in bone 0.4% when compared to baseline and 0.5% to 0.6% com-
mineral density at the lumbar spine and the hip. An increase in pared to placebo. HbA1c lowering, however, was not observed
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fractures by about 30% was observed in patients on canagliflozin in a single monotherapy clinical trial comparing colesevelam
in a pooled analysis of 8 clinical trial (mean duration 68 weeks). It to placebo. Colesevelam use is associated with ~20%
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increase in triglyceride levels. Other adverse effects include

is likely that the effect on the bones is a class effect and not
constipation and dyspepsia.
restricted to canagliflozin. A modest increase in upper limb frac-
With their modest glucose lowering and significant side
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tures was observed with canaglifloxin therapy. It is not known if effects, using bromocriptine or colesevelam to treat diabetes
this is due to an effect on bone strength or related to falls due to is not recommended.
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hypotension. All the SGLT2 inhibitors cause a modest increase in

LDL cholesterol levels (3%-8%). Also, in clinical trials, patients Drug Combinations
taking dapagliflozin had higher rates of breast cancer (nine cases Several drug combinations are available in different dose sizes
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vs none in comparator arms) and bladder cancer (10 cases vs 1 in

including glyburide-metformin (Glucovance), glipizide-metformin
placebo arm). These cancer rates exceeded the expected rates in
(Metaglip), repaglinide-metformin (Prandi-Met), rosiglitazone-
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age-matched reference diabetes population.

metformin (Avandamet), pioglitazone-metformin (ACTOplus
Cases of diabetic ketoacidosis have been reported with off label
Met), rosiglitazone and glimepiride (Avandaryl), pioglitazone and
use of SGLT2 inhibitors in patients with type 1 diabetes. Type 1
glimepiride (Duetact), sitagliptin-metformin (Janumet), saxagliptin-
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patients are taught to give less insulin if their glucose levels are not
metformin extended release (kombiglyze XR), linagliptin and
elevated. SGLT2 inhibitors lower glucose levels by changing the
metformin (Jentadueto), alogliptin and metformin (Kazano),
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renal threshold for glucose reabsorption (ie, increased glucosuria)

alogliptin and pioglitazone (Oseni), dapagliflozin and metformin
and not through insulin action. Type 1 patients on an SGLT2
(Xigduo), canagliflozin and metformin (Invokamet), empa-
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inhibitor, because the glucose levels are not elevated, may either
gliflozin and metformin (Synjardy), empagliflozin and linagliptin
withhold or reduce their insulin doses to such a degree as to induce
(Glyxambi), and lixisenatide and insulin glargine (Soliqua). These
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ketoacidoisis, SGLT2 inhibitors should not be used in patients with

combinations, however, limit the clinician’s ability to optimally
type 1 diabetes and in those patients labeled as having type 2 diabe-
adjust dosage of the individual drugs and for that reason are not
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tes but who are very insulin deficient and ketosis-prone. recommended.
6. OTHERS 7. INSULIN
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Insulin is indicated for individuals with type 1 diabetes as well as

a. Pramlintide is a synthetic analog of islet amyloid polypep-
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for those with type 2 diabetes whose hyperglycemia does not

tide (IAPP) that when given subcutaneously (1) delays gas-
tric emptying, (2) suppresses glucagon secretion, and (3) respond to diet therapy and other diabetes drugs.
decreases appetite. It is approved for use both in type 1 and Human insulin is dispensed as either regular (R) or Neutral
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insulin-treated type 2 patients. In 6-month clinical studies Protamine Hagedorn (NPH) formulations. Animal insulins are no
with type 1 and insulin-treated type 2 patients, those on the longer available in the United States. Six analogs of human insu-
drug had approximately a 0.4% reduction in HbA1c and lost lin—three rapidly acting (insulin lispro, insulin aspart, and insulin
at
about 1.7 kg compared to placebo. The HbA1c reduction glulisine) and three long-acting (insulin glargine, insulin detemir,
was sustained for 2 years, but some of the weight was
and insulin degludec) are available for clinical use. All currently
regained. The drug is given immediately before the meal by
e
injection. Hypoglycemia is the most concerning adverse available insulins contain less than 10 ppm of proinsulin and are
event, and it is recommended that the short-acting or pre- labeled as “purified.” These purified insulins preserve their
mixed insulin doses be reduced by 50% when the drug is potency, so that refrigeration is recommended but not crucial.
started. Since the drug slows gastric emptying, recovery from During travel, reserve supplies of insulin can be readily trans-
hypoglycemia can be a problem because of delay in absorp- ported for weeks without losing potency if protected from
tion of the fast-acting carbohydrate. Nausea was the other extremes of heat or cold. All the insulins in the United States are
main side effect, affecting 30% to 50% of subjects. It tended
available in a concentration of 100 U/mL (U100) and dispensed
to improve with time. In patients with type 1 diabetes,
pramlintide is initiated at the dose of 15 μg before each meal in 10 mL vials or 0.3 mL cartridges or prefilled disposable pens.
and titrated by 15 μg increments to a maintenance dose of Several insulins are now available at higher concentrations—insulin
30 or 60 μg before each meal. In patients with type 2 glargine 300 U/mL (U300), insulin degludec 200 U/mL (U200),

Glucose utilization rate (mg/kg/h) 6 TABLE 17–13 Summary of bioavailability

characteristics of the insulins.
5
Insulin Onset of Peak Effective
4 NPH Preparations Action Action Duration
3 Insulins lispro, 5-15 min 1-1.5 h 3-4 h
Detemir aspart, glulisine
2 Degludec
Glargine Human regular 30-60 min 2h 6-8 h
1
Technosphere 5-15 min 1h 3h
0 inhaled insulin
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0 10 20 30
Human NPH 2-4 h 6-7 h 10-20 h
Time (h) after SC injection
Insulin glargine 0.5-1 h Flat ~24 h
ev
End of
Insulin detemir 0.5-1 h Flat 17 h
observation period
Insulin degludec 0.5-1.5 h Flat >42 h
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Glucose infusion rate (mg/kg/min)
800
700
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600
insulin are particularly useful in the treatment of diabetic keto-
500 Regular acidosis and during the perioperative management of insulin-
insulin
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400 requiring diabetics.

300 For very insulin-resistant subjects who would otherwise require
Insulin
op
200 aspart large volumes of insulin solution, a U500 preparation of human

100 regular insulin is available both in a vial form and a disposable
0 pen. If the vial form is used, a U500 insulin syringe is available to
y
0 120 240 360 480 600 measure doses. The disposable pen dispenses the regular insulin in
Time (min) 5 unit increments.
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0.2 IU/kg SQ
B. Rapidly acting insulin analogs Insulin lispro (Huma-
o
FIGURE 17–12 Extent and duration of action of various types log) is an insulin analog where the proline at position B28 is
of insulin (in a fasting diabetic). Duration of action may be extended
reversed with the lysine at B29. Insulin aspart (Novolog) is a single
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considerably when the dose of a given insulin formulation increases

above the average therapeutic doses depicted here.
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TABLE 17–14 Insulin preparations available in the

a
insulin lispro 200 U/mL (U200), and regular insulin 500 U/mL United States.
(U500). (Figure 17–12; Tables 17–13 and 17–14).
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It is important to recognize that values given for time of onset Short Acting Insulin Preparations
Insulin lispro (Humalog, Lilly)
of action, peak effect, and duration of action are only approximate Insulin aspart (Novolog, Novo Nordisk)
up
and that there is great variability in these parameters from patient Insulin glusisine (Apidra, Sanofi Aventis)
to patient and even in a given patient depending on the size of the Regular insulin (Lilly, Novo Nordisk)
Technosphere inhaled regular insulin (Afrezza, Mannkind)
dose, the site of injection, the degree of exercise, the avidity of
lic
circulating anti-insulin antibodies, and other less well-defined Long acting Insulin Preparations
NPH insulin (Lilly, Novo Nordisk)
variables. Insulin glargine (Lantus, Sanofi Aventis)
at
Insulin detemir (Levemir, Novo Nordisk)

Short-Acting Insulin Preparations Insulin degludec (Tresiba, Novo Nordisk)
Premixed Insulins
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The short-acting preparations are regular insulin and the rapidly 70% NPH/30% regular (70/30 insulin, Lilly, Novo Nordisk)
acting insulin analogs. They are dispensed as clear solutions at 75% insulin lispro/protamine (NPL) 25% insulin lispro
neutral pH and contain small amounts of zinc to improve their (Humalog Mix 75/25, Lilly)
50% NPL/50% insulin lispro (Humalog Mix 50/50, Lilly)
stability and shelf life. 70% insulin aspart/protamine/30% insulin aspart
(Novolog Mix 70/30, Novo Nordisk)
A. Regular insulin Regular insulin is a short-acting, soluble 70% insulin degludec/30% insulin aspart
(Ryzodeg, Novo Nordisk)
crystalline zinc insulin whose hypoglycemic effect appears
within 30 minutes after subcutaneous injection, peaks at about a
All types of insulin available in the United States are recombinant human or human
insulin analog origin. All the insulins are dispensed at U100 concentration. There is an
2 hours, and lasts for about 5 to 7 hours when usual quantities additional U500 preparation of regular insulin; U300 preparation of insulin glargine;
(ie, 5-15 U) are administered. Intravenous infusions of regular U200 preparations of insulin lispro and insulin degludec.

substitution of proline by aspartic acid at position B28. In Insulin refrigerated when not in use and if bottles were discarded
glulisine (Apidra) the asparagine at position B3 is replaced by after 1 month of use. Patients should be vigilant for early
lysine and the lysine in position B29 by glutamic acid. These three signs of frosting or clumping of the NPH insulin, because it
analogs have less tendency to form hexamers compared to human indicates a pronounced loss of potency. Several cases of dia-
betic ketoacidosis have been reported in patients with type
insulin. When injected subcutaneously, the analogs quickly dis- 1 diabetes who had been inadvertently injecting this dena-
sociate into monomers and are absorbed very rapidly, reaching tured insulin.
peak serum values in as soon as 1 hour—in contrast to regular b. Insulin glargine is an insulin analog in which the aspara-
human insulin, whose hexamers require considerably more time to gine at position 21 of the A chain of the human insulin
dissociate and become absorbed. The amino acid changes in these molecule is replaced by glycine and two arginines are added
analogs do not interfere with their binding to the insulin receptor, to the carboxyl terminal of the B chain. The arginines raise
with the circulating half-life, or with their immunogenicity, which the isoelectric point of the molecule close to neutral, making
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are all identical to those of human regular insulin. it more soluble in an acidic environment. In contrast,
human insulin has an isoelectric point of pH 5.4. Insulin
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Clinical trials have demonstrated that the optimal times of glargine is a clear insulin that, when injected into the neutral
preprandial subcutaneous injection of comparable doses of the pH environment of the subcutaneous tissue, forms micro-
rapid-acting insulin analogs and of regular human insulin are 20 precipitates that slowly release the insulin into the circula-
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minutes and 60 minutes before the meal, respectively. Although tion. It lasts for about 24 hours without any pronounced
this more rapid onset of action has been welcomed as a great peaks and is given once a day to provide basal coverage. This
insulin cannot be mixed with the other insulins because of
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convenience by patients with diabetes who object to waiting as

its acidic pH. When this insulin was given as a single injec-
long as 60 minutes after injecting regular human insulin before tion at bedtime to type 1 diabetes patients, fasting hypergly-
they can begin their meal, patients must be taught to ingest cemia was better controlled when compared with bedtime
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adequate absorbable carbohydrate early in the meal to avoid NPH insulin. The clinical trials also suggest that there may
hypoglycemia during the meal. Another desirable feature of rap- be less nocturnal hypoglycemia with this insulin when com-
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idly acting insulin analogs is that their duration of action pared with NPH insulin.
remains at about 4 hours irrespective of dosage. This contrasts In one clinical trial involving patients with type 2 diabe-
with regular insulin, whose duration of action is prolonged when tes, insulin glargine was associated with a slightly more rapid
y
larger doses are used. progression of retinopathy when compared with NPH insu-
lin. The frequency was 7.5% with the analog and 2.7% with
The rapidly acting analogs are also commonly used in pumps.
the NPH. This observation, however, was not confirmed in
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In a double-blind crossover study comparing insulin lispro with a 5-year open label prospective study of 1024 subjects ran-
regular insulin in insulin pumps, persons using insulin lispro had domized to NPH or insulin glargine. In in vitro studies,
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lower HbA1c values and improved postprandial glucose control insulin glargine has a sixfold greater affinity for the IGF-1
with the same frequency of hypoglycemia. In the event of pump receptor compared with the human insulin. There has also
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failure, however, users of the rapidly acting insulin analogs will been a report that insulin glargine has increased mitogenic-
have more rapid onset of hyperglycemia and ketosis. ity compared with human insulin in a human osteosarcoma
cell line. Circulating levels of insulin glargine, however, are
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While insulin aspart has been approved for intravenous use (eg, low, and the clinical significance of these observations is not
in hyperglycemic emergencies), there is no advantage in using yet clear. An observational study from Germany of 127,031
insulin aspart over regular insulin by this route. A U200 concen- patients who had exposure to regular insulin, short-acting
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tration of insulin lispro is available in a disposable prefilled pen. insulin analogs, and insulin glargine reported a strong cor-
The only advantage of the U200 over the U100 insulin lispro relation between increased insulin dose and cancer risk.
up
preparation is that it delivers the same dose in half the volume. Moreover insulin glargine, dose for dose, appeared to carry
a higher risk than regular insulin. Subsequent epidemiologic
Long-Acting Insulin Preparations studies, however, failed to confirm this observation. A more
concentrated form of insulin glargine (U300) is available as
lic
a. Neutral Protamine Hagedorn (NPH), or isophane, insulin an insulin pen. In pharmacodynamic studies in type 1
is an intermediate-acting insulin in which the onset of action patients, the U300 compared to the U100 preparation had
is delayed by combining two parts of soluble crystalline zinc approximately 5 hours longer duration of action. In clinical
at
insulin with one part protamine zinc insulin. The mixture trials in type 1 patients, U300 use did not result in better
has equivalent concentrations of protamine and insulin, so control or reduce the rates of hypoglycemia. Although lim-
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that neither is in excess (isophane). Its onset of action is ited clinical data suggest that insulin glargine is safe in preg-
delayed by 2 to 4 hours, and its peak response is generally nancy, it is not approved for this use.
reached in about 8 to 10 hours. Because its duration of c. Insulin detemir is an insulin analog in which the threonine
action is often less than 24 hours (with a range of 10-20 at position 30 of the B chain has been removed and a 14-C
hours), most patients require at least two injections daily to fatty acid chain (tetradecanoic acid) is attached to the lysine
maintain a sustained insulin effect. at position 29 by acylation. The fatty acid chain makes the
Flocculation of suspended particles may occasionally frost molecule more lipophilic than native insulin, and the addi-
the sides of a bottle of NPH insulin or clump within bottles tion of zinc stabilizes the molecule and leads to formation of
from which multiple small doses are withdrawn over a pro- hexamers. After injection, self-association at the injection
longed period. This instability is a rare phenomenon and site and albumin binding in the circulation via the fatty acid
might occur less frequently if NPH human insulin were side chain lead to slower distribution to peripheral target

tissues and prolonged duration of action. The affinity of insulin mixture and can be given within 15 minutes before or after
insulin detemir is four- to fivefold lower than that of human starting a meal. Similarly, a 70% insulin aspart protamine/30%
soluble insulin and, therefore, the U100 formulation of insulin aspart (NovoLogMix 70/30) is now available. The main
insulin detemir has a concentration of 2400 nmol/mL com- advantages of these new mixtures are that (1) they can be given
pared to 600 nmol/mL for NPH. The duration of action for
insulin detemir is about 17 hours at therapeutically relevant within 15 minutes of starting a meal and (2) they are superior in
doses. It is recommended that the insulin is injected once or controlling the postprandial glucose rise after a carbohydrate-rich
twice a day to achieve a stable basal coverage. Apparently this meal. These benefits have not translated into improvements in
insulin has been reported to have lower within-subject phar- HbA1c levels when compared with the usual 70% NPH/30%
macodynamic variability compared to NPH insulin and regular mixture.
insulin glargine. In vitro studies do not suggest any clinically The longer-acting insulin analogs, insulin glargine or insulin
relevant albumin binding interactions between insulin detemir, cannot be acutely mixed with either regular insulin or the
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detemir and fatty acids or protein-bound drugs. Because

there is a vast excess (~400,000) of albumin-binding sites rapid-acting insulin analogs. Insulin degludec, however, can be
mixed and is available as 70% insulin degludec/30% insulin aspart
ev
available in plasma per insulin detemir molecule, it is

unlikely that hypoalbuminemic disease states will affect the and is injected once or twice a day.
ratio of bound to free insulin detemir.
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d. I nsulin degludec In this insulin analog, the threonine at Methods of Insulin Administration
position B30 has been removed and the lysine at position
B29 is conjugated to hexadecanoic acid via a gamma-L- a. Insulin syringes and needles—Disposable plastic syringes
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glutamyl spacer. In the vial, in the presence of phenol and with needles attached are available in 1-mL (100 units), 0.5-mL
zinc, the insulin is in the form of dihexamers but when (50 units), and 0.3-mL (30 units) sizes. The “low-dose”
injected subcutaneously, it self-associates into large multi- 0.3 mL syringes are popular because many patients with
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hexameric chains consisting of thousands of dihexamers. diabetes do not take more than 30 units of insulin in a single
The chains slowly dissolve in the subcutaneous tissue and injection except in rare instances of extreme insulin resis-
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insulin monomers are steadily released into the systemic tance. Three lengths of needles are available: 6 mm, 8 mm,
circulation. The half-life of the insulin is 25 hours. Its onset and 12.7 mm. Long needles are preferable in obese patients
of action is in 30 to 90 minutes and its duration of action is to reduce variability of insulin absorption. The needles are of
28, 30, and 31 gauges. The 31 gauge needles are almost
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more than 42 hours. It is recommended that the insulin be

injected once or twice a day to achieve a stable basal cover- painless. Many patients reuse the syringes up to 3 to 5 times,
age. Insulin degludec is available in two concentrations, maintaining adequate sterility by recapping between uses.
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U100 and U200 and dispensed in prefilled disposable pens. Any part of the body covered by loose skin can be used as
an injection site, including the abdomen, thighs, upper
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arms, flanks, and upper-outer quadrants of the buttocks.

Insulin Mixtures Cleaning with alcohol is not necessary as long as the skin is
Patients with type 2 diabetes can sometimes achieve reasonable clean. Rotation of sites is recommended to avoid delayed
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glucose control with just prebreakfast and presupper injections of aborption when lipohypertrophy occurs from repeated use
of a single site. In general, regular insulin is absorbed more
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mixtures of short acting and NPH insulins. The regular insulin or

rapidly acting insulin analog is withdrawn first, then the NPH rapidly from upper regions of the body such as the deltoid
area or the abdomen rather than from the thighs or but-
insulin and then injected immediately. Stable premixed insulins tocks. Exercise appears to facilitate insulin absorption when
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(70% NPH and 30% regular) are available as a convenience to the injection site is adjacent to the exercising muscle. For
patients who have difficulty mixing insulin because of visual prob- most patients, the abdomen is the recommended region for
up
lems or insufficient manual dexterity. injection because it provides a considerable area in which to
With increasing use of rapid-acting insulin analogs as a pre- rotate sites, and there may be less variability of absorption
prandial insulin, it has become evident that combination with an with exercise than when the thigh or deltoid areas are used.
The effect of anatomic regions appears to be much less pro-
lic
intermediate-acting or long-acting insulin is essential to maintain

nounced with the analogs.
postabsorptive glycemic control. It has been demonstrated that
b. Insulin pen injector devices—Insulin pens eliminate the
insulin lispro can be acutely mixed with NPH insulin without need for carrying insulin vials and syringes. Cartridges of
at
affecting its rapid absorption. Premixed preparations of insulin insulin lispro, insulin aspart, and insulin glargine are avail-
lispro and NPH insulin however are unstable because of exchange able for reusable pens (Lilly, Novo Nordisk, and Owen
e
of insulin lispro with the human insulin in the protamine com- Mumford). Disposable prefilled pens are also available for
plex. Consequently, over time, the soluble component becomes a regular insulin (U100 and U500), insulin lispro, insulin
mixture of regular and insulin lispro at varying ratios. In an aspart, insulin glulisine, insulin detemir, insulin glargine,
attempt to remedy this, intermediate insulin composed of iso- insulin degludec, NPH, 70% NPH/30% regular, 75%
NPL/25% insulin lispro, 50% NPL/50% insulin lispro,
phane complexes of protamine with insulin lispro was developed 70% insulin aspart protamine/30% insulin aspart, and 70%
and given the name NPL (neutral protamine lispro). Premixed insulin degludec/30% insulin aspart. Pen needles are avail-
combinations of NPL and insulin lispro are now available for able in 29, 31, and 32 gauges and 4, 5, 6, 8, and 12.7 mm
clinical use (Humalog Mix 75/25 and Humalog Mix 50/50). lengths.
These mixtures have a more rapid onset of glucose-lowering activ- c. Insulin pumps—In the United States, Medtronic Min-
ity compared with 70% NPH/30% regular human iMed, Insulet, Animas, Roche, and Tandem make battery

operated subcutaneous insulin infusion pumps. These combined with basal insulin was as effective in glucose low-
pumps are small (about the size of a pager) and easy to pro- ering as rapid-acting insulin analogs combined with basal
gram. They have many features, including the ability to insulin. It is formulated as a single use color coded cartridge
record a number of different basal rates throughout a delivering 4, 8, or 12 units immediately before the meal.
24-hour period and adjust the time over which bolus doses The manufacturer provides a dose conversion table; patients
are given. They are able also to detect pressure build-up if injecting up to 4 units of rapid-acting insulin analog should
the catheter is kinked. The catheter connecting the insulin use the 4 unit cartridge. Those injecting 5 to 8 units should
reservoir to the subcutaneous cannula can be disconnected use the 8-unit cartridge. If the dose is 9 to 12 units of rapid-
so the patient can remove the pump temporarily (eg, for acting insulin premeal then one 4-unit cartridge and one
bathing). Ominpod (Insulet Corporation) is an insulin infu- 8-unit cartridge or one 12-unit cartridge should be used.
sion system in which the insulin reservoir and infusion set The inhaler is about the size of a referee’s whistle.
are integrated into one unit (pod), so there is no catheter The most common adverse reaction of the inhaled insulin
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(electronic patch pump). The pod, placed on the skin, deliv- was a cough affecting about 27% of patients. A small
ers subcutaneous basal and bolus insulin based on wirelessly decrease in pulmonary function (forced expiratory volume
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transmitted instructions from a personal digital assistant. in 1 second [FEV1]) was seen in the first 3 months of use,
The great advantage of continuous subcutaneous insu- which persisted over 2 years of follow-up. Inhaled insulin is
lin infusion (CSII) is that it allows for establishment of a contraindicated in smokers and patients with chronic lung
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basal profile tailored to the patient allowing for better over- disease, such as asthma and chronic obstructive pulmonary
night and between meals glucose control. The ability to disease. Spirometry should be performed to identify poten-
adjust the basals makes it easier for the patient to manage tial lung disease prior to initiating therapy. During the clini-
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glycemic excursions that occur with exercise. The pumps cal trials, there were two cases of lung cancer in patients who
have software that can assist the patient to calculate boluses were taking inhaled insulin and none in the comparator-
based on glucose reading and carbohydrates to be con- treated patients. All the patients in whom lung cancer devel-
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sumed. They also keep track of the time elapsed since last oped had a history of prior cigarette smoking. There were
insulin bolus and the patient is reminded of this when he or also two cases of squamous cell carcinoma of the lung in
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she attempts to give additional correction bolus before the nonsmokers exposed to inhaled insulin; these cases occurred
effect of the previous bolus has worn off (insulin on board after completion of the clinical trials. Cases of lung cancer
feature). This feature reduces the risk of overcorrecting and were also reported in cigarette smokers using a previously
y
subsequent hypoglycemia. available inhaled insulin preparation (Exubera). The inci-

CSII therapy is appropriate for patients who are moti- dence rate in the Exubera treated group was 0.13 per 1000
vated, mechanically adept, educated about diabetes (diet, patient years and 0.03 per 1000 patient years in the compar-
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insulin action, treatment of hypo- and hyperglycemia), and ator-treated group.

willing to monitor their blood glucose four to six times a e. P ancreas transplantation—Type 1 patients who are candi-
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day. Known complications of CSII include ketoacidosis, dates for a kidney transplant should be evaluated for a pan-
which can occur when insulin delivery is interrupted, and creas transplant. Contraindications include age greater than
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skin infections. Another major disadvantage is the cost and 55 years old, uncorrectable coronary artery disease; extensive
the time demanded of physicians and staff in initiating peripheral vacular disease, and significant obesity (weight
therapy. Almost all patients use the rapid-acting insulin >100 kg). The pancreas transplant may occur simultane-
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analogs in their pumps. Clinical trials have shown that when ously (simultaneous pancreas/kidney) or after kidney trans-
compared with regular insulin, subjects using rapid-acting plant (pancreas after kidney).
insulin analogs in pumps had lower HbA1c values and Patients undergoing simultaneous pancreas and kidney
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improved postprandial glucose control with the same fre- transplantation have an 85% chance of pancreatic graft
quency of hypoglycemia. survival at 1 year and 69% at 5 years. Solitary pancreatic
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V-go (Valeritas) is a mechanical patch pump designed transplantation in the absence of a need for renal transplan-
specifically for people with type 2 diabetes who employ a tation should be considered only in those rare patients who
basal/bolus insulin regimen. The device is preset to deliver fail all other insulin therapeutic approaches and who have
lic
one of three fixed and flat basal rates (20, 30, or 40 units) frequent severe hypoglycemia or who have life-threatening
for 24 hours (at which point it must be replaced) and there complications related to their lack of metabolic control.
is a button that delivers two units per press to help cover Pancreas transplant alone graft survival is 78% at 1 year and
at
meals. 54% at 5 years.

d. I nhaled insulin—Technosphere insulin (Afrezza) is a dry- f. Islet cell transplantation—Total pancreatectomy is curative
powder formulation of regular insulin that can be inhaled. for severe pain syndrome associated with chronic pancreati-
e
It consists of 2 to 2.5 μm crystals of the excipient, fumaryl tis. The pancreatectomy, however, results in surgical diabetes.
diketopiperazine, that provide large surface area for adsorp- Harvesting islets from the removed pancreas and autotrans-
tion of proteins like insulin. Pharmacokinetic studies show planting them into the liver (via portal vein) can prevent the
that technosphere insulin is rapidly absorbed with peak development of diabetes or result in “mild” diabetes (partial
insulin levels reached in 12 to 15 minutes and declining to islet function) that is easier to manage. Since the islets are
baseline in 3 hours. Pharmacodynamic studies show that autologous, no immunosuppression is required. The number
median time to maximum effect with inhaled insulin is of islets transplanted is the main predictor of insulin
approximately 1 hour and declines to baseline by about 3 hours. independence.
In contrast, the median time to maximum effect with sub- People with type 1 diabetes can become insulin indepen-
cutaneous insulin lispro is about 2 hours and declines to dent after receiving an islet cell transplant. The islets are
baseline by 4 hours. In clinical trials, technosphere insulin isolated from a donor pancreas (alloislet transplant). The

islets are infused into the portal vein using a percutaneous glycosuria. For the occasional patient, measurement of ICA 512,
transhepatic approach, and they lodge in the liver releasing GAD, insulin and zinc transporter 8 antibodies can help in distin-
insulin in response to physiologic stimuli. Long-term guishing between type 1 and type 2 diabetes. Many newly diag-
immunosuppression is necessary to prevent allograft rejec- nosed patients with type 1 diabetes still have significant endogenous
tion and to suppress the autoimmune process that led to the
disease in the first place. Insulin independence for more insulin production, and C-peptide levels may not reliably distin-
than 5 years has been demonstrated in patients who got guish between type 1 and type 2 diabetes. Other baseline labora-
anti-CD3 antibody or anti-thymocyte globulin for induc- tory measurements that should be made part of the record include
tion of immunosuppression and calcineurin inhibitors, hemoglobin A1c, lipid profile, serum creatinine and electrolytes,
mTor inhibitors, and mycophenolate mofetil as mainte- complete blood count, electrocardiogram, and urine albumin
nance immunosuppression. One major limitation is the measurement (type 2 patient).
need for more than one islet infusion to achieve insulin
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independence. This is because of significant loss of islets

during isolation and the period prior to engraftment. Allois- Patient Education and Self-Management
ev
let transplantation is currently an experimental procedure Training

and widespread application will depend on improving insu-
lin independence rates with one infusion and also demon- Since diabetes is a lifelong disorder, education of the patient and
the family is probably the most important obligation of the clini-
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strating that the long-term outcomes are as good as those of

pancreas transplant alone. cian who provides initial care. The best persons to manage a dis-
ease that is affected so markedly by daily fluctuations in
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environmental stress, exercise, diet, and infections are the patients

STEPS IN THE MANAGEMENT OF THE themselves and their families. It must be remembered that educa-
DIABETIC PATIENT
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tion is necessary not only for patients with newly diagnosed dia-
betes and their families, but also for patients with diabetes of any
History and Examination
op
duration who may never have been properly educated about their
disorder or who may not be aware of advances in diabetes manage-
A complete history is taken and physical examination is per-
ment. The teaching curriculum should include explanations by the
formed for diagnostic purposes and to rule out the presence of
y
physician or nurse of the nature of diabetes and its potential acute

coexisting or complicating disease. Nutritional status should be
and chronic hazards and how they can be recognized early and
noted, particularly if catabolic features such as progressive weight
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prevented or treated. Self-monitoring of blood glucose should be

loss are present despite a normal or increased food intake. The
emphasized, especially in insulin-requiring diabetic patients, and
family history should include not only the incidence but also the
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instructions must be given on proper testing and recording of

age at onset of diabetes in other members of the family, and it
data. Patients must also be helped to accept the fact that they have
should be noted whether affected family members were obese,
diabetes; until this difficult adjustment is made, efforts to cope
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whether they required insulin, and whether they developed com-

with the disorder are likely to be futile. Counseling should be
plications from their diabetes. Other factors that increase cardio-
directed at avoidance of extremes such as compulsive rigidity or
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vascular risk, such as a smoking history, presence of hypertension

self-destructive neglect.
or hyperlipidemia, or oral contraceptive pill use should be
Patients on insulin should have an understanding of the actions
documented.
of basal and bolus insulins. They should be taught how to deter-
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A careful physical examination should include baseline height

mine whether the basal dose is appropriate and how to adjust the
and weight, pulse rate, and blood pressure. If obesity is present,
up
rapidly acting insulin dose for the carbohydrate content of a meal.

it should be characterized as to its distribution, and a waist-to-
Patients and their families or friends should also be taught to recog-
hip ratio should be recorded. All peripheral arterial pulses should
nize signs and symptoms of hypoglycemia and how to institute
be examined, noting whether bruits or other signs of atheroscle-
lic
appropriate therapy for hypoglycemic reactions. Strenuous exercise

rotic disease are present. Neurologic and ophthalmologic exami-
can precipitate hypoglycemia, and patients should know how much
nations should be performed, with emphasis on investigation of
to reduce their insulin dosage in anticipation of strenuous activity
abnormalities that may be related to diabetes, such as neovascu-
at
or to take supplemental carbohydrate. Injection of insulin into a site

larization of the retina or stocking/glove sensory loss in the
farthest away from the muscles most involved in exercise may help
extremities.
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ameliorate exercise-induced hypoglycemia, since insulin injected in

the proximity of exercising muscle may be more rapidly mobilized.
Laboratory Diagnosis Exercise training also increases the effectiveness of insulin and insu-
Laboratory diagnosis should include documentation of the pres- lin doses should be adjusted accordingly. Because infections, par-
ence of fasting hyperglycemia (plasma glucose ≥126 mg/dL ticularly pyogenic ones with fever and toxemia, provoke a marked
[7 mmol/L]), postprandial (post-glucose tolerance test) values consis- increase in insulin requirements, patients must be taught how to
tently greater than or equal to 200 mg/dL (11.1 mmol/L) or appropriately administer supplemental rapid-acting insulin as
HbA1c greater than or equal to 6.5%. An attempt should be made needed to correct hyperglycemia during infections.
to characterize the diabetes as type 1 or type 2, based on the clini- Type 2 diabetes on noninsulin medications should be informed
cal features present and on whether ketonuria accompanies the about the time of onset, peak action, duration of action, and any

adverse effects of pharmacologic agents being used. They should TABLE 17–15 Examples of intensive insulin
also learn to inquire about possible drug interactions whenever regimens using rapid-acting insulin
any new medications are added to their regimens. analogs (insulin lispro, aspart, or
The targets for blood glucose control should be elevated appro- glulisine) and NPH, or insulin detemir,
priately in elderly patients since they have the greatest risk if sub- glargine or degludec in a 70-kg man
jected to hypoglycemia and the least long-term benefit from more with type 1 diabetes.a-c
rigid glycemic control. Patients should be provided advice on
Prebreakfast Prelunch Predinner Bedtime
personal hygiene, including detailed instructions on foot and den-
tal care. All infections (especially pyogenic ones) provoke the Rapid- 5U 4U 6U —
acting
release of high levels of insulin antagonists such as catecholamines insulin
or glucagon and thus bring about a marked increase in insulin
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analog
requirements. Patients who use oral agents may decompensate and NPH insulin 3U 3U 2U 8-9 U
temporarily require insulin. All patients receiving therapy that can
ev
OR
cause hypoglycemia should wear a MedicAlert bracelet or necklace
that clearly states that insulin or an oral sulfonylurea drug is being Rapid- 5U 4U 6U —
acting
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taken. Patients should be told about community agencies, such as insulin

American Diabetes Association chapters, that can serve as a con- analog
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tinuing source of instruction. Insulin — — — 15-16 U

Finally, vigorous efforts should be made to persuade new dia- glargine
betics who smoke to give up the habit, since large vessel peripheral or
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degludec
vascular disease and debilitating retinopathy are less common in Insulin 6-7 U — — 8-9 U
nonsmoking diabetic patients. detemir
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a
Assumes that patient is consuming approximately 75 g carbohydrate at break-
Specific Therapy fast, 60 g at lunch, and 90 g at dinner.
b
The dose of rapid-acting insulin analogs can be raised by 1 or 2 U if extra carbohy-
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A reasonable aim of therapy is to approach normal glycemic excur- drate (15-30 g) is ingested or if premeal blood glucose is >170 mg/dL. The rapid-
sions without provoking severe or frequent hypoglycemia. Criteria acting insulin analogs can be mixed in the same syringe with NPH insulin.
c
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for “acceptable” control includes the following: (1) blood glucose Insulin glargine or insulin detemir must be given as a separate injection.
levels of 90 to 130 mg/dL (5-7.2 mmol/L) before meals and after

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an overnight fast, (2) levels no higher than 180 mg/dL (10

mmol/L) 1 hour after meals and 150 mg/dL (8.3 mmol/L) 2 A combination of rapid-acting insulin analogs and long-acting
hours after meals, and (3) HbA1c levels less than 7% for nonpreg- insulins (insulin glargine or insulin detemir or insulin degludec)
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nant adults. Less stringent HbA1c goals may be appropriate in allows for more physiologic insulin replacement. In clinical stud-
children, those with a history of severe hypoglycemia, limited life
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ies, combinations of rapid-acting insulin analogs (insulin lispro or

expectancy, and advanced microvascular and macrovascular dis- insulin aspart) with meals together with intermediate-acting
ease. In the elderly frail patient, an HbA1c target of approximately (NPH) or longer-acting insulin (insulin glargine) for basal cover-
8% (preprandial blood glucose levels in the range of the 150-159
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age have now been shown to have improved HbA1c values with less
mg/dL) may be reasonable although formal evidence is lacking. hypoglycemia when compared with a regimen of regular insulin
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with meals and NPH at night. Table 17–15 illustrates some regi-
A. Type 1 diabetes At the onset of type 1 diabetes, many mens that might be appropriate for a 70-kg person with type 1
patients recover some pancreatic β cell function and may tempo- diabetes eating meals of standard carbohydrate intake and moder-
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rarily need only low doses of exogenous insulin to supplement ate to low fat content.
their own endogenous insulin secretion. This is known as the Multiple injections of NPH insulin can be mixed in the same
honeymoon period. Within 8 weeks to 2 years, however, most of syringe as the insulin lispro, insulin aspart, and insulin glulisine.
at
these patients show either absent or negligible pancreatic β cell Insulin glargine or degludec are usually given once in the evening
function. At this point, these patients should be switched to a to provide 24-hour coverage. There are occasional patients in
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more flexible insulin regimen with a combination of rapid-acting whom insulin glargine does not seem to last for 24 hours, and in
insulin analogs or regular insulin together with intermediate- such cases it needs to be given twice a day. Insulin detemir does
acting or long-acting insulin. At a minimum, the patient should not last for 24 hours and usually has to be given twice a day. The
be on a three-injection regimen and frequently may need four long acting insulin analogs cannot be mixed with any of the other
or more injections. Twice-daily split-dose insulin mixtures cannot insulins and must be given as a separate injection.
maintain near-normalization of blood glucose without hypoglyce- Continuous subcutaneous insulin infusion by portable battery-
mia (particularly at night) and are not recommended. Self- operated open loop insulin pumps currently provides the most
monitoring of blood glucose levels is required for determining the flexible approach, allowing the setting of different basal rates
optimal adjustment of insulin dosage and the modulation of food throughout the 24 hours and permitting bolus dose adjustment by
intake and exercise in type 1 diabetes. as little as 0.05 unit increments. The 24-hour basal dosage is

usually based on age and body weight. An adolescent might need Prebreakfast hyperglycemia due to the Somogyi effect can be
as much as 0.4 U/kg/d; young adult (<25 years) 0.35 U/kg/d; and treated by reducing the dose of either intermediate- or long-acting
older adults 0.25 U/kg/d. For example, a 70-kg 30-year-old man insulin analog at bedtime. For hyperglycemia due to waning of
may require a basal rate of 0.7 U/h throughout the 24 hours with overnight basal insulin and/or dawn phenomenon, an increase in
the exception of 3 am to 8 am, when 0.8 U/h might be appropriate the evening dose of the basal insulin or shifting it from dinnertime
(to accomodate the dawn phenomenon). The dawn phenomenon is to bedtime (or both) can be effective. A bedtime dose either of
more pronounced in the adolescent and young adult. The meal insulin glargine or insulin detemir provides more sustained over-
bolus also varies based on the time of day and the person’s age. night insulin levels than human NPH and may be effective in
Adolesecents and young adults usually require 1 unit for about 10 g managing refractory prebreakfast hyperglycemia. If this fails, insu-
carbohydrate. Older adults usually require about 1 unit for 15 g lin pump therapy may be required with a higher basal insulin
carbohydrate. The correction factor—how much insulin is needed infusion rate (eg, from 0.8 U/h to 0.9 U/h from 6 am until
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to lower glucose levels by 50 mg/dL can be calculated from the breakfast).

insulin-to-carbohydrate ratios. For example, if 1 unit is required Metformin use in type 1 diabetes patients has been shown to
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for 15 g carbohydrate, then 1 unit will lower glucose levels by reduce the total daily insulin doses and promote weight loss but
50 mg/dL. If on the other 1.5 units of insulin is required for 15 g does not improve glucose control. GLP-1 receptor agonists simi-
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of carbohydrate (ie, 1 unit for 10 g carbohydrate), then 1.5 units larly have been demonstrated to promote weight loss and reduce
of insulin will lower glucose levels by 50 mg/dL (ie, 1 unit will insulin doses in type 1 patients but not improve glucose control.
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lower glucose level by 33 mg/dL). For a 70-kg 30-year-old man, 1

unit per 15 g of carbohydrate plus 1 U for 50 mg/dL of blood B. Type 2 diabetes Therapeutic recommendations are based
glucose above a target value (eg, 120 mg/dL) is a common starting on the relative contributions of β cell insufficiency and insulin
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point. Further adjustments to basal and bolus dosages would insensitivity in individual patients. The possibility that the indi-
depend on the results of blood glucose monitoring. Most patients vidual patient has a specific etiological cause for their diabetes
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use the rapid-acting insulin analogs in the pumps. should always be considered, especially when the patient does not
One of the more difficult therapeutic problems in managing have a family history of type 2 diabetes or does not have any evi-
patients with type 1 diabetes is determining the proper adjustment dence of central obesity or insulin resistance. Such patients should
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of insulin dose when the early morning blood glucose level is high be evaluated for other types of diabetes such as LADA or MODY.
before breakfast (Table 17–16). Prebreakfast hyperglycemia is Patients with LADA should be prescribed insulin when their dis-
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sometimes due to the Somogyi effect, in which nocturnal hypogly- ease is diagnosed and treated like patients with type 1 diabetes. It
cemia evokes a surge of counterregulatory hormones to produce is also important to note that many type 2 patients have a progres-
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high blood glucose levels by 7 am. However, a more common sive loss of β cell function and will require additional therapeutic
cause of prebreakfast hyperglycemia is the waning of the evening interventions with time.
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or bedtime insulin and/or the dawn phenomenon. That is, Weight reduction—One of the primary modes of therapy in
reduced tissue sensitivity to insulin between 5 am and 8 am the obese patient with type 2 diabetes is weight reduction. Nor-
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(dawn), due to spikes of growth hormone released hours before, at malization of glycemia can be achieved by reducing adipose stores,
onset of sleep. Table 17–16 shows that diagnosis of the cause of with consequent restoration of tissue sensitivity to insulin. A
prebreakfast hyperglycemia can be facilitated by self-monitoring combination of caloric restriction, increased exercise, modification
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of blood glucose at 3 am in addition to the usual bedtime and 7 am of behavior, and consistent reinforcement of good eating habits is
measurements. This is required for only a few nights, and when a required if a weight reduction program is to be successful. Under-
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particular pattern emerges from monitoring blood glucose levels standing the risks and complications of diabetes may motivate the
overnight, appropriate therapeutic measures can be taken. patient to lose weight.
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TABLE 17–16 Typical patterns of overnight blood glucose levels and serum-free immunoreactive insulin levels
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in prebreakfast hyperglycemia due to various causes in patients with type 1 diabetes.
Serum-Free Immunoreactive
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Blood Glucose Levels (mg/dL) Insulin Levels (μU/mL)
10 pm 3 am 7 am 10 pm 3 am 7 am
Somogyi effect 90 40 200 High Slightly high Normal

Dawn phenomenon 110 110 150 Normal Normal Normal
Waning of circulating insulin levels plus 110 190 220 Normal Low Low
dawn phenomenon
Waning of circulating insulin levels plus 110 40 380 High Normal Low
dawn phenomenon plus Somogyi effect

For selected patients, medical or surgical options for weight greater in the study of obese people without diabetes (4.1%).
loss should be considered (also see Chapter 20). Orlistat, phenter- Serious neuropsychiatric events and seizures have been reported in
mine/topiramate, naltrexone/extended-release bupropion, and patients taking bupropion. Naltrexone should not be given to
high-dose liraglutide (3 mg daily) are weight loss medications patients receiving long-term opioid therapy. Naltrexone/extended
approved for use in combination with diet and exercise. bupropion should be discontinued if the patient needs intermit-
Orlistat is a reversible inhibitor of gastric and pancreatic tent opiate therapy. Patients should be warned that they may be
lipases and prevents the hydrolysis of dietary triglycerides. These more sensitive to opiates after the naltrexone/extended bupropion
triglycerides are then excreted in the feces. In a 1-year study in preparation has been discontinued.
obese patients with type 2 diabetes, those taking orlistat had lost Liraglutide 3 mg (Saxenda) is a GLP-1 receptor agonist. The
more weight, had lower HbA1c values, and had improved lipid 0.6 to 1.8 mg dose has been approved for the treatment of type 2
profiles. The main adverse reactions were gastrointestinal, with diabetes and is associated with modest weight loss. The 3-mg dose
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oily spotting, oily stool, flatus, and fecal urgency and frequency. has been approved for weight loss in combination with diet and
Malabsorption of fat-soluble vitamins also occurs. Patients exercise. In nondiabetic obese persons, liraglutide together with
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should take a multivitamin tablet containing fat-soluble vita- diet and exercise resulted in 4.5% more weight loss than placebo
mins at least 2 hours before or 2 hours after the administration at 1 year of treatment. In a study of people with diabetes, the aver-
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of orlistat. Cases of severe liver injury have been reported with age weight loss with the medication was 3.7% compared to pla-
this drug although a cause and effect relationship has not been cebo at 1 year. Common adverse reactions include nausea,
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established. vomiting, and diarrhea. Serious side effects include pancreatitis.

Phentermine is a sympathomimetic amine that stimulates The medication should not be used in patients with MEN 2 or
release of norepinephrine in the hypothalamus. Topiramate is personal or family history of medullary thyroid cancer.
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primarily used as an anticonvulsant, but it also appears to reduce Bariatric surgery (Roux-en-Y, gastric sleeve, biliopancreatic
appetite. In a 56-week phase 3 study, an extended-release prepara- diversion/duodenal switch, or gastric banding) typically result in
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tion of phentermine/topiramate (Qsymia), together with diet and substantial weight loss, and improvement in glucose levels. A
lifestyle intervention, resulted in 10 kg weight loss (9.8%) com- meta-analysis examining the impact of bariatric surgery on
pared to 1.4 kg (1.2%) with placebo. As might be expected, the patients with diabetes and BMI of 40 kg/m2 or greater noted that
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diabetes subgroup on active therapy had greater reductions in 82% of patients had resolution of clinical and laboratory manifes-
HbA1c levels and fewer patients with prediabetes on active therapy tations of diabetes in the first 2 years after surgery and 62%
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progressed to diabetes. The adverse events are consistent with remained free of diabetes more than 2 years after surgery. The
those of the constituent drugs. The most common adverse reac- improvement was most marked in the procedure that caused the
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tions were paresthesia, dizziness, dysgeusia, insomnia, constipa- greatest weight loss (biliopancreatic diversion/duodenal switch).
tion, and dry mouth. Topiramate can worsen depression and There was, however, a high attrition of patients available for fol-
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increase risk of suicidal thoughts. It is also teratogenic and the low-up, and there was little information about different ethnic
FDA has required the manufacturer to conduct a risk evaluation types. Weight regain does occur after bariatric surgery, and it can
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and mitigation strategy (REMS). The medication is only available be expected that 20% to 25% of the lost weight will be regained
through specialty mail-order pharmacies. over 10 years. The impact of this weight gain on diabetes recur-
Lorcaserin (Belviq) is a 5-hydroxytryptamine receptor subtype rence depends principally on the degree of beta cell dysfunction.
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2C (5-HT2C) agonist. This receptor subclass regulates mood and Also anatomic changes imposed by malabsorptive surgery can
appetite. In a 52-week study, patients taking lorcaserin had a 8.1-kg result in protein malnutrition, vitamin, and mineral deficiencies.
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weight loss (8.2%) compared to 3.2 kg in the placebo group Clinically significant deficiencies in calcium, folic acid, iron, and
(3.3%). The main adverse reactions were headache and nausea. vitamins D, B12, A, and K are common. Thus, patients undergo-
Fenfluramine, an agonist for the 5-HT2B receptor, was associated ing malabsorptive procedures require lifelong supplementation
lic
with serotonin-related cardiac valvulopathy. Activation of the and monitoring by a team familiar with possible deficiencies. Both
5-HT2C receptor, however, does not appear to be associated with early and late dumping symptoms can also occur.
valvulopathy. Sibutramine, a combined serotonin-norepinephrine Nonobese patients with type 2 diabetes frequently have
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reuptake inhibitor, was moderately effective in promoting weight increased visceral adiposity—the so-called metabolically obese
loss, but it was withdrawn from the U.S. market because of its normal-weight patient. There is less emphasis on weight loss but
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association with increased cardiovascular risk. exercise remains an important aspect of treatment.
Naltrexone is an antagonist at mu- and kappa-opioid receptors Antihyperglycemic agents—Figure 17–13 outlines the treat-
and is used in the treatment of alcohol and opioid dependence. ment approach based on the consensus algorithm proposed by the
Bupropion is a partial agonist at the mu-opioid receptor, an American Diabetes Association and the European Association for
antagonist at the kappa-opioid receptor and a partial agonist at the the Study of Diabetes. The current recommendation is to start
nociception receptor; it is used to treat depression, seasonal affec- metformin therapy at diagnosis and not wait to see if the patient
tive disorder, and as an aid to stop smoking. Naltrexone/extended- can achieve target glycemic control with weight management and
release bupropion (Contrave), together with diet and exercise in exercise. Metformin is advantageous because, apart from lowering
patients with diabetes, resulted in 2% more weight loss than pla- glucose without the risk of hypoglycemia, it also lowers triglycer-
cebo at 1 year of study. The weight loss with the medication was ides and promotes some modest weight loss. The drug, however,

Weight loss + exercise + metformin

*
Metformin + another agent
*
Metformin + two other agents
*
Metformin + more complex insulin
regimen ± other non-insulin agent
*If needed to reach individualized HbA1c target after ~3 months

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Seven main classes of agents: metformin, sulfonylureas (includes

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nateglinide, repaglinide), thiazolidinediones, GLP-1 receptor agonists,

DPP-4 inhibitors, SGLT2 inhibitors, insulins (alpha-glucosidase inhibitors,
colesevelam, pramlintide, bromocriptine not included because of limited
efficacy and significant adverse reactions).
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In making a therapeutic decision (single agent or in combination) take into account

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efficacy; hypoglycemia risk; effect on weight; major side effects; cost. The DPP-4
inhibitors are of moderate efficacy whereas all the other agents are of high efficacy.
Sulfonylureas and insulins have increased risk of hypoglycemia. Metformin and
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DPP-4 inhibitors are weight neutral; GLP-1 receptor agonists, SGLT2 inhibitors
promote weight loss; and sulfonylureas, insulins and thiazolidinediones are
associated with weight gain. Metformin can cause lactic acidosis. Thiazolidinediones
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are associated with fluid retention, fracture risk and possibly bladder cancer.
GLP-1 receptor agonists are associated with nausea and vomiting and possibly
pancreatitis. DPP-4 inhibitors may increase pancreatitis risk. SGLT inhibitors are
associated with genital mycotic infections, urinary tract infections, and hypotension.
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All the agents with the exception of metformin and sulfonylureas are expensive.
Insulins are expensive if you take into consideration the additional costs of
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monitoring.
FIGURE 17–13 Suggested algorithm for the treatment of type 2 diabetes based partly on the recommendations of the consensus panel
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of the American Diabetes Association/European Association for the Study of Diabetes. (Data from Inzucchi SE, Bergenstal RM, Buse JB, et al.
Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes
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Association and the European Association for the Study of Diabetes. Diabetologia. 2015 Mar;58(3):429-442.)
cannot be used in patients with renal or liver failure, and some `-glucosidase inhibitors have modest glucose-lowering effects
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patients have gastrointestinal side effects at even the lowest doses. and have gastrointestinal side effects. They have a lower risk of
Under these circumstances the choice of the initial agent depends hypoglycemia than the sulfonylureas and promote weight loss.
on a number of factors, including comorbid conditions, adverse The GLP-1 receptor agonists have a lower risk of hypoglycemia
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reactions to the medications, ability of the patient to monitor for than the sulfonylureas, and they promote weight loss. However,
hypoglycemia, drug cost, and patient and physician preferences.
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they need to be given by injection, cause nausea, may cause pan-

Sulfonylureas have been available for many years, and their creatitis, and are contraindicated in patients with gastroparesis.
use in combination with metformin is well established. They do, The DPP-4 inhibitors also have a low risk of hypoglycemia, and
however, have the propensity to cause hypoglycemia and weight
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they do not cause nausea or vomiting. They can also be used in

gain. Thiazolidinediones improve peripheral insulin resistance patients with kidney impairment. There are, however, reports of
and lower glucose without causing hypoglycemia. They also have serious allergic reactions, including anaphylaxis, angioedema, and
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been reported to improve nonalcoholic fatty liver disease. In addi- Stevens-Johnson syndrome. There is concern that they, like the
tion, they have beneficial effects on the lipid profile and some GLP-1 receptor agonists, may cause pancreatitis. The SGLT2
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other cardiovascular risk factors. They decrease microalbuminuria, inhibitors lower fasting and postprandial glucose levels. They also
and reduce neointimal tissue hyperplasia after coronary artery have a low risk of hypoglycemia, promote weight loss, and lower
stent placement. Thiazolidinediones, however, can cause fluid blood pressure levels. They increase the risk for mycotic genital
retention and are contraindicated in patients with heart failure. infections, urosepsis and possibly fractures. They can also cause
They also very commonly increase weight, which patients find volume depletion and are less effective in patients with kidney
distressing, affecting adherence. The drugs are associated with disease.
increased fracture risk in women and this adverse effect signifi- When patients are not well controlled on their initial therapy
cantly limits their use. Both drugs are contraindicated in patients (usually metformin) then a second agent should be added. In
with active liver disease and in patients with liver enzyme levels those patients where the problem is hyperglycemia after a carbo-
more than or equal to 2.5 times the upper limit of normal. The hydrate-rich meal (such as dinner), a short-acting secretagogue

before meals may suffice to put the glucose levels into the target sensitivity can be to the insulin or to the additives–protamine or
range. Patients with severe insulin resistance or nonalcoholic fatty cresol. Because sensitivity was often due to noninsulin protein
liver disease or microalbuminuria may be candidates for a thiazoli- contaminants, the highly purified insulins have markedly reduced
dinedione. Subjects who are very concerned about weight gain the incidence of insulin allergy, especially of the local variety. Anti-
may benefit from a trial of a GLP-1-receptor agonist, DPP-4 histamines, corticosteroids, and even desensitization may be
inhibitor, or SGLT2 inhibitor. If two agents are inadequate, then required, especially for systemic hypersensitivity in an insulin-
a third agent is added, although data on efficacy with such com- dependent patient. Rituximab followed by Omalizumab was
bined therapy are limited. When the combination of oral agents reported to be successful in one patient with severe refractory
(and injectable GLP-1 receptor agonists) fail to achieve target insulin allergy. A trial of insulin analogs should also be considered.
glycemic control in patients with type 2 diabetes or if there are There is a case report of successful use of insulin lispro in the face
contraindications to their use, then insulin treatment should be of generalized allergy to human insulin.
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instituted. Various insulin regimens may be effective. One pro-

posed regimen is to continue the oral combination therapy and
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B. Immune insulin resistance All patients who receive

then simply add a bedtime dose of NPH or long-acting insulin insulin (including insulin analogs) develop a low titer of circulat-
analog to reduce excessive nocturnal hepatic glucose output and ing IgG antibodies, and this neutralizes the rapid action of insulin
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improve fasting glucose levels. If the patient does not achieve tar- to a small extent. With the animal insulins, a high titer of circulat-
get glucose levels during the day, then daytime insulin treatment ing antibodies is sometimes developed, resulting in extremely high
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can be initiated. A convenient insulin regimen under these cir- insulin requirements, often to more than 200 U/d. This is now
cumstances is a split dose of 70/30 NPH/regular mixture (or very rarely seen with the switch to the highly purified human
Humalog Mix 75/25 or NovoLogMix 70/30) before breakfast and insulins and has not been reported with use of the analogs.
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before dinner. If this regimen fails to achieve satisfactory glycemic

goals or is associated with unacceptable frequency of hypoglyce- C. Lipodystrophy at injection sites Rarely, a disfiguring
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mic episodes, then a more intensive regimen of multiple insulin atrophy of subcutaneous fatty tissue occurs at the site of insulin
injections can be instituted as in patients with type 1 diabetes. injection. Although the cause of this complication is obscure, it
Metformin principally reduces hepatic glucose output, and it is seems to represent a form of immune reaction, particularly
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reasonable to continue with this drug when insulin therapy is because it occurs predominantly in females and is associated with
instituted. The thiazolidinediones, which improve peripheral lymphocyte infiltration in the lipoatrophic area. This complica-
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insulin sensitivity, can be used together with insulin, but this com- tion has become even less common because of the development of
bination is associated with more weight gain and peripheral highly purified insulin preparations of neutral pH. Injection of
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edema. The sulfonylureas, the GLP-1-receptor agonists, and the highly purified preparations of insulin directly into the atrophic
DPP-4 inibitors also have been shown to be of continued benefit. area often results in restoration of normal contours.
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Weight-reducing interventions should continue even after initia- Lipohypertrophy, on the other hand, is not a consequence of
tion of insulin therapy and may allow for simplification of the immune responses; rather, it seems to be due to the pharmacologic
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therapeutic regimen in the future. effects of depositing insulin in the same location repeatedly (Figure
17–14). It is prevented by rotation of injection sites. There is a
IMMUNOPATHOLOGY OF INSULIN
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THERAPY
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At least five molecular classes of insulin antibodies are produced

during the course of insulin therapy: IgA, IgD, IgE, IgG, and
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IgM. Human insulin is much less antigenic than the older formu-
lations of animal (especially beef ) insulins, but because of its hexa-
meric presentation at therapeutic injection doses, it is also treated as a
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foreign substance by the immune system and results in detectable—

albeit low—titers of insulin antibodies in most patients.
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A. Insulin allergy Insulin allergy, a hypersensitivity reaction

of the immediate type, is a rare condition in which local or sys-
temic urticaria occurs immediately after insulin injection. This
reaction is due to histamine release from tissue mast cells sensi-
tized by adherence of IgE antibodies to their surface. In severe
cases, anaphylaxis can occur. The appearance of a subcutaneous
nodule at the site of insulin injection, occurring several hours after
the injection and lasting for up to 24 hours, has been attributed to FIGURE 17–14 Lipohypertrophy due to overuse of insulin infu-
an IgG-mediated complement-binding Arthus reaction. The sion sites.

case report of a male patient who had intractable lipohypertrophy adaptation of the central nervous system to recurrent hypoglycemic
(fatty infiltration of injection site) with human insulin but no episodes is due to changes in glucose transportation or metabolism.
longer had the problem when he switched to insulin lispro. It has been shown that hypoglycemic unawareness can be reversed
by keeping glucose levels high for a period of several weeks. Except
ACUTE COMPLICATIONS OF for sweating, most of the sympathetic symptoms of hypoglycemia
are blunted in patients receiving β-blocking agents for angina pec-
DIABETES MELLITUS toris or hypertension. Though not absolutely contraindicated,
these drugs must be used with caution in insulin-requiring diabet-
Hypoglycemia ics, and β1-selective blocking agents are preferred.
Hypoglycemic reactions (see Chapter 18) are the most common Hypoglycemia in insulin-treated patients with diabetes occurs
complications that occur in patients with diabetes who are treated as a consequence of three factors: behavioral issues, impaired
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with insulin. It can also occur in any patient taking oral agents counterregulatory systems, and complications of diabetes.
that stimulate pancreatic β cells (eg, sulfonylureas, meglitinide, Behavioral issues include injecting too much insulin for the
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d-phenylalanine analogs), particularly if the patient is elderly and amount of carbohydrates ingested. Drinking alcohol in excess,
has renal or liver disease. It occurs more frequently with the use of especially on an empty stomach, can also cause hypoglycemia. In
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long-acting sulfonylureas. patients with type 1 diabetes, hypoglycemia can occur during or
The signs and symptoms of hypoglycemia may be divided into even several hours after exercise, and so glucose levels need to be
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those resulting from stimulation of the autonomic nervous system monitored and food and insulin adjusted. Some patients do not
and those arising from neuroglycopenia (insufficient glucose for like their glucose levels to be high, and they treat every high glu-
normal central nervous system function). When the blood glucose cose level aggressively. These individuals who stack their insulin,
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falls to around 54 mg/dL (3 mmol/L), the patient starts to experi- that is, give another dose of insulin before the first injection has
ence both sympathetic (tachycardia, palpitations, sweating, tremu- had its full action, can develop hypoglycemia.
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lousness) and parasympathetic (nausea, hunger) nervous system Counterregulatory issues resulting in hypoglycemia include
symptoms. If these autonomic symptoms are ignored and the impaired glucagon response and impaired sympathoadrenal
glucose levels fall further (to around 50 mg/dL [2.8 mmol/L]), responses (Table 17–18). Patients with diabetes of greater than
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then neuroglycopenic symptoms appear, including irritability, confu- 5 years duration lose their glucagon response to hypoglycemia. As
sion, blurred vision, tiredness, headache, and difficulty speaking. a result, they are at a significant disadvantage in protecting them-
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A further decline in glucose (below 30 mg/dL [1.7 mmol/L]) can selves against falling glucose levels. Once the glucagon response is
then lead to loss of consciousness or even a seizure. lost, their sympathoadrenal responses take on added importance.
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With repeated episodes of hypoglycemia, there is adaptation Unfortunately, aging, autonomic neuropathy, or hypoglycemic
and autonomic symptoms do not occur until the blood glucose unawareness due to repeated low glucose levels further blunts the
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levels are much lower and so the first symptoms are often due to sympathoadrenal responses. Occasionally, Addison disease devel-
neuroglycopenia. This condition, which is referred to as hypogly- ops in persons with type 1 diabetes mellitus; when this happens,
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cemic unawareness, results from failure of the sympathetic ner- insulin requirements fall significantly, and unless insulin dose is
vous system to respond to hypoglycemia (Table 17–17). This reduced, recurrent hypoglycemia will develop.
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TABLE 17–17 Hypoglycemic “unawareness” in type TABLE 17–18 Counterregulatory responses to

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1 diabetes mellitus. hypoglycemia.
I. Sleeping patient (nocturnal hypoglycemia) Defective Counterregulation in

Type 1 Diabetesa
lic
II. Hypoglycemia with unawareness while awake Normal Counterregulation

A. Manifestations
Glucagon rises rapidly to three Glucagon response to insulin-
a. Neuroglycopenic symptoms first (weakness, lethargy,
to five times baseline after induced hypoglycemia is lost
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confusion, incoordination, blurred vision)

insulin-induced hypoglyce- after onset of type 1 diabetes
b. Autonomic symptoms are delayed and blunted
mia, provoking hepatic
(tremor, anxiety, palpitations, sweating, hunger)
glycogenolysis
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B. Mechanisms
1. Defective autonomic response: Adrenergic discharge (1) raises Blunted or absent adrenergic
a. Adaptation to chronic hypoglycemia (increased brain hepatic glucose output by response may occur as a result
glucose transporter I) glycogenolysis and (2) pro- of:
b. Due to diabetic autonomic neuropathy vides warning to subject of (1) Neural damage associated
C. Management impending hypoglycemic with advanced age or auto-
1. Identify patients at risk and reevaluate glycemic goals crisis nomic neuropathy
2. Advise frequent self-monitoring of blood glucose; use of (2) Neural dysfunction (iatrogenic)
continuous glucose monitoring systems from frequent hypoglycemia
3. Learn to detect subtle symptoms of neuroglycopenia a
4. Avoid recurrent hypoglycemia Type 2 diabetics are less well characterized as to their defective counterregulation of
5. Injectable glucagon made available to family glucagon loss, but appear to have the same frequency and causes of adrenergic loss
as do type 1 diabetics.

Complications of diabetes that increase the risk for hypogly- If the patient is hypoglycemic from use of a long-acting oral
cemia include autonomic neuropathy, gastroparesis, and renal hypoglycemic agent (eg, chlorpropamide or glyburide) or from
failure. The sympathetic nervous system is an important system high doses of a long-acting insulin, admission to hospital for treat-
alerting the individual that the glucose level is falling by causing ment with continuous intravenous glucose and careful monitoring
symptoms of tachycardia, palpitations, sweating, and tremulous- of blood glucose is indicated.
ness. Failure of the sympathoadrenal responses increases the risk of
hypoglycemia. In patients with gastroparesis, insulin given before Coma
a meal promotes maximal glucose uptake into cells before the food
Coma is a medical emergency calling for immediate evaluation to
is absorbed, causing the glucose levels to fall. Finally, in renal fail-
determine its cause so that proper therapy can be started. Patients
ure, hypoglycemia can occur presumably because of decreased
with diabetes may be comatose because of hypoglycemia, diabetic
insulin clearance as well as loss of the renal contribution to gluco-
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ketoacidosis, hyperglycemic hyperosmolar coma, or lactic acidosis.

neogenesis in the postabsorptive state.
When evaluating a comatose diabetic patient, these must be con-
To treat insulin-induced hypoglycemia, the diabetic patient
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sidered in addition to the myriad causes included in the differen-

should carry glucose tablets or juice at all times. For most epi-
tial diagnosis of coma (eg, cerebrovascular accidents, head trauma,
sodes, ingestion of 15 g of carbohydrate is sufficient to reverse the
intoxication with alcohol, or other drugs).
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hypoglycemia. The patient should be instructed to check the

After emergency measures have been instituted (airway protec-
blood glucose in 15 minutes and treat again if the glucose level is
tion; laboratory tests; intravenous dextrose unless fingerstix blood
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still low.
glucose shows hyperglycemia), a careful history (from family,
A parenteral glucagon emergency kit (1 mg) should be pro-
friends, or paramedics), physical examination, and laboratory
vided to every patient with diabetes who is on insulin therapy.
evaluation are required to resolve the differential diagnosis.
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Family or friends should be instructed how to inject it subcutane-

ously or intramuscularly into the buttock, arm, or thigh in the Patients in deep coma from a hyperosmolar nonketotic state or
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event that the patient is unconscious or refuses food. The drug can from hypoglycemia are generally flaccid and have quiet breathing—
occasionally cause vomiting and the unconscious patient should in contrast to patients with acidosis, whose respirations are rapid
be turned on his or her side to protect the airway. Glucagon mobi- and deep if the pH of arterial blood has dropped to 7.1 or below.
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lizes glycogen from the liver raising the blood glucose by about When hypoglycemia is a cause of the coma, the state of hydration
36 mg/dL (2 mmol/L) in about 15 minutes. After the patient is usually normal. Although the clinical laboratory remains the
final arbiter in confirming the diagnosis, a rapid estimate of blood
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recovers consciousness additional oral carbohydrate should be

glucose and ketones can be obtained by the use of bedside glucose
given. Glucagon is contraindicated in sulfonylurea-induced hypo-
and ketone meters (see Laboratory Findings in diabetes mellitus,
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glycemia where it paradoxically causes insulin release. People with

discussed earlier). Table 17–19 is a summary of some laboratory
diabetes on hypoglycemic drug therapy should also wear a Medi-
abnormalities found in diabetic patients with coma attributable to
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cAlert bracelet or necklace or carry a card in his or her wallet.

diabetes or its treatment.
Medical personnel treating severe hypoglycemia can give 50 mL of
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50% glucose solution by rapid intravenous infusion. If intrave-

nous therapy is not available, 1 mg of glucagon can be injected 1. DIABETIC KETOACIDOSIS
intramuscularly. If the patient is stuporous and glucagon is not This acute complication of diabetes mellitus may be the first
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available, small amounts of honey or maple syrup or glucose gel manifestation of previously undiagnosed type 1 diabetes or may
(15 g) can be inserted within the buccal pouch, although, in gen- result from increased insulin requirements in type 1 diabetes
up
eral, oral feeding is contraindicated in unconscious patients. Rectal patients during the course of infection, trauma, myocardial infarc-
administration of maple syrup or honey (30 mL per 500 mL of tion, or surgery. The National Data Group reports an annual
warm water) has been effective. incidence of five to eight episodes of diabetic ketoacidosis per
lic
Most patients who arrive at emergency departments in hypo- 1000 diabetic patients. In all cases, precipitating factors such as
glycemic coma appear to recover fully; however, profound hypo- infection should be searched for and treated appropriately. Poor
glycemia or delays in therapy can result in permanent neurologic
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compliance, either for psychological reasons or because of inade-

deficit or even death. Furthermore, repeated episodes of hypo- quate patient education, is probably the most common cause of
glycemia may have a cumulative adverse effect on intellectual recurrent diabetic ketoacidosis.
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functioning. The physician should carefully review with the Diabetic ketoacidosis has been found to be one of the more
patient the events leading up to the hypoglycemic episode. Asso- common serious complications of insulin pump therapy, occur-
ciated use of other medications, as well as alcohol or narcotics, ring in approximately 1 per 80 patient-months of treatment.
should be noted. Careful attention should be paid to diet, exer- Patients with type 2 diabetes may also develop ketoacidosis
cise pattern, insulin or sulfonylurea dosage, and general compli- under severe stress such as sepsis, trauma, or major surgery.
ance with the prescribed diabetes treatment regimen. Any factors
thought to have contributed to the development of the episode
should be identified and recommendations made in order to Pathogenesis
prevent recurrences of this potentially disastrous complication of Acute insulin deficiency results in rapid mobilization of energy
diabetes therapy. from stores in muscle and fat depots, leading to an increased flux

TABLE 17–19 Summary of some laboratory abnormalities in patients with coma directly attributable to
diabetes or its treatment.
Urine Plasma
Glucose Ketones Glucose Bicarbonate Ketones Osmolality
Diabetic ketoacidosis ++ to ++++ ++++ High Low ++++ +++

Hyperglycemic nonketotic ++ to ++++ 0 or +a High Normal or 0 ++++
coma slightly lowb
c
Hypoglycemia 0 0 or + Low Normal 0 Normal
Lactic acidosis 0 to + 0 or + Normal, low, or Low 0 or + Normal
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high
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a
A small degree of ketonuria may be present if the patient is severely stressed or has not been eating because of illness.
b
A patient may be acidotic if there is severe volume depletion with cardiovascular collapse or if sepsis is present.
c
Leftover urine in bladder might still contain sugar from earlier hyperglycemia.
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of amino acids to the liver for conversion to glucose and of fatty patient with rapid and deep respirations and the fruity breath odor
acids for conversion to ketones (acetoacetate, β-hydroxybutyrate, of acetone strongly suggest the diagnosis. Postural hypotension
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and acetone). In addition to this increased availability of precur- with tachycardia indicates profound dehydration and salt deple-
sor, there is a direct effect of the low insulin-glucagon ratio on the tion. Abdominal pain and even tenderness may be present in the
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liver that promotes increased production of ketones as well as of absence of abdominal disease, and mild hypothermia is usually
glucose. In response to both the acute insulin deficiency and the present.
metabolic stress of ketosis, the levels of insulin-antagonistic hor-
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mones (corticosteroids, catecholamines, glucagon, and GH) are B. Laboratory findings Typically, the patient with moder-
consistently elevated. Furthermore, in the absence of insulin,
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ately severe diabetic ketoacidosis has a plasma glucose of 350 to

peripheral utilization of glucose and ketones is reduced. The com- 900 mg/dL (19.4-50 mmol/L), serum ketones are positive at a
bination of increased production and decreased utilization leads to dilution of 1:8 or greater and β-hydroxybutryate levels are
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an accumulation of these substances in blood, with plasma glucose 4 mmol/L or higher, hyperkalemia of 5 to 8 mEq/L, slight hypo-
levels reaching 500 mg/dL (27.8 mmol/L) or more and plasma natremia of approximately 130 mEq/L, hyperphosphatemia of
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ketones reaching levels of 8 to 15 mmol/L or more. 6 to 7 mg/dL, and an elevated blood urea nitrogen and creatinine.
β-Hydroxybutyrate is the predominant ketone and its ratio to Acidosis may be severe (pH ranging from 6.9-7.2 with a bicarbon-
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acetoacetate increases from 1:1 to as much as 5:1. ate concentration ranging from 5 to 15 mEq/L); pCO2 is low
The hyperglycemia causes osmotic diuresis leading to depletion (15-20 mm Hg) secondary to hyperventilation. The difference
of intravascular volume. As this progresses, impaired renal blood between venous and arterial pH is 0.02 to 0.15 pH units and the
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flow reduces the kidney’s ability to excrete glucose, and hyperos- difference in venous and arterial bicarbonate is 1.88 mEq/L. These
molality worsens. Severe hyperosmolality (>330 mOsm/kg) cor- small differences will not affect either the diagnosis or the management
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relates closely with central nervous system depression and coma. of diabetic ketoacidosis, and there is no need to collect arterial
In a similar manner, impaired renal excretion of hydrogen ions
blood for measuring the acid-base status. The fluid depletion is
aggravates the metabolic acidosis that occurs as a result of the
typically about 100 mL/kg.
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accumulation of the ketoacids, β-hydroxybutyrate, and acetoace-

tate. The accumulation of ketones may cause vomiting, which The hyperkalemia occurs despite total body potassium deple-
exacerbates the intravascular volume depletion. In addition, pro- tion, because of the shift of potassium from the intracellular to
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longed acidosis can compromise cardiac output and reduce vascu- extracellular spaces in systemic acidosis. The average total body
lar tone. The result may be severe cardiovascular collapse with potassium deficit resulting from osmotic diuresis, acidosis, and
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gastrointestinal losses is about 3 to 5 mEq/kg body weight. Simi-

generation of lactic acid, which then adds to the already existent
larly, despite the elevated serum phosphate, total body phosphate
metabolic acidosis.
is generally depleted. Serum sodium is generally reduced, due to
loss of sodium ions by polyuria and vomiting (7-10 mEq/kg), and
Clinical Features because severe hyperglycemia shifts intracellular water into the
A. Symptoms and signs The appearance of diabetic keto- extracellular compartment (for every 100 mg/dL of plasma glu-
acidosis is usually preceded by a day or more of polyuria and cose above normal, serum sodium decreases by 1.6 mEq/L [5.56
polydipsia associated with marked fatigue, nausea, and vomiting. mmol/L]). Hypertriglyceridemia should be considered if the cor-
Eventually, mental stupor ensues and can progress to frank coma. rected sodium is very low. Serum osmolality can be directly mea-
On physical examination, evidence of dehydration in a stuporous sured by standard tests of freezing point depression or can be

estimated by calculating the molarity of sodium, chloride, and those with severe DKA are stuporous, have pH less than 7.0 and
glucose in the serum. A convenient formula for estimating effective β-hydroxybutyrate levels of greater than 8 mmol/L. Those with
serum osmolality is: mild DKA can be treated in the emergency room, but those with
moderate or severe DKA require admission to the intensive care
Glucose (mg/dL) unit or step-down unit.
mOsm/kg = 2[measured Na + ] +
18 The therapeutic goals are to restore plasma volume and tissue
perfusion; reduce blood glucose and osmolality toward normal;
The effective serum osmolality in humans is generally between correct acidosis; replenish electrolyte losses; and identify and treat
280 and 300 mOsm/kg. These calculated estimates are usually 10 precipitating factors. Gastric intubation is recommended in the
to 20 mOsm/kg lower than values recorded by standard cryo- comatose patient to prevent vomiting and aspiration that may
scopic techniques. Central nervous depression or coma occurs occur as a result of gastric atony, a common complication of dia-
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when the effective serum osmolality exceeds 320 to 330 mOsm/L. betic ketoacidosis. In patients with preexisting cardiac or renal
Blood urea nitrogen and serum creatinine are invariably ele- failure or those in severe cardiovascular collapse, a central venous
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vated because of dehydration. Urea exerts an effect on freezing pressure catheter or a Swan-Ganz catheter should be inserted to
point depression as measured in the laboratory, but it is freely evaluate the degree of hypovolemia and to monitor subsequent
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permeable across cell membranes and therefore not included in fluid administration.
calculations of effective serum osmolality. Serum creatinine may A comprehensive flow sheet that includes vital signs, serial
also be falsely elevated due to interference from acetoacetate with
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laboratory data, and therapeutic interventions (eg, fluids, insulin)

some automated creatinine assays. However, most laboratories can should be meticulously maintained by the clinician responsible for
correct for these interfering chromogens by using a more specific the patient’s care. Plasma glucose should be recorded hourly and
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method, if asked to do so. electrolytes and pH at least every 2 to 3 hours during the initial
The nitroprusside reagents (Acetest and Ketostix) used for the treatment period. A bedside glucose meter should be used to
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bedside assessment of ketoacidemia and ketoaciduria measure titrate the insulin therapy. The patient should not receive sedatives
only acetoacetate and its by-product, acetone. The sensitivity of or opioids in order to avoid masking signs and symptoms of
these reagents for acetone, however, is quite poor, requiring over impending cerebral edema.
y
10 mmol/L. This level is seldom reached in the plasma of ketoaci-

dotic subjects—although this detectable concentration is readily 1. Fluid replacement. In most adult patients, the fluid deficit is
4 to 5 L. Once the diagnosis of diabetic ketoacidosis is estab-
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achieved in urine. Thus, in the plasma of ketotic patients, only

lished in the emergency department, administration of at least
acetoacetate is measured by these reagents. The more prevalent 2 L of isotonic saline (0.9% saline solution) in an adult patient
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β-hydroxybutyrate has no ketone group and is therefore not in the first 2 to 3 hours is necessary to help restore plasma
detected by the conventional nitroprusside tests. This takes on volume and stabilize blood pressure while acutely reducing the
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special importance in the presence of circulatory collapse during hyperosmolar state. In addition, by improving renal plasma
diabetic ketoacidosis, wherein an increase in lactic acid can shift flow, fluid replacement also restores the renal capacity to
excrete hydrogen ions, thereby ameliorating the acidosis as
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the redox state to increase β-hydroxybutyrate at the expense of the

readily detectable acetoacetate. Bedside diagnostic reagents would well. After the first 2 L of fluid have been given, the intrave-
nous infusion should be at a rate of 300 to 400 mL/h. Use
then be unreliable, suggesting no ketonemia in cases where 0.9% saline unless the serum sodium is greater than 150 mEq/L
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β-hydroxybutyrate is a major factor in producing the acidosis. when 0.45% (“half normal”) saline should be used. Failure to
Combined bedside glucose and ketone meters (Precision Xtra, give sufficient volume replacement (at least 3-4 L in 8 hours)
up
Nova Max Plus) that measure blood β-hydroxybutyrate concen- to restore normal perfusion is one of the most serious therapeu-
tration on capillary blood are now available. Many clinical labora- tic shortcomings affecting satisfactory recovery. In the same
tories also offer direct blood β-hydroxybutyrate measurement. way, excessive fluid replacement (>5 L in 8 hours) may contrib-
ute to acute respiratory distress syndrome or cerebral edema.
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Nonspecific elevations of serum amylase and lipase occur in

When blood glucose falls to approximately 250 mg/dL
about 16% to 25% of cases of diabetic ketoacidosis, and an imag- (13.9 mmol/L), the fluids should be changed to a 5% glucose
ing study may be necessary if the diagnosis of acute pancreatitis is containing solution to maintain plasma glucose in the range of
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being seriously considered. Leukocytosis as high as 25,000/mL 250 to 300 mg/dL (13.9-16.7 mmol/L). This prevents the
with a left shift may occur with or without associated infection. development of hypoglycemia and also reduces the likelihood
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The presence of an elevated or even a normal temperature would of cerebral edema, which may result from a too rapid decline
suggest the presence of an infection, since patients with diabetic of blood glucose.
ketoacidosis are generally hypothermic if uninfected. 2. Insulin treatment. Immediately after the initiation of fluid
replacement and determination that the patient’s serum potas-
sium is more than 3.5 mEq/L, a bolus of 0.1 U/kg can be given
Treatment intravenously to prime the tissue insulin receptors. This inhib-
its both gluconeogenesis and ketogenesis while promoting
Patients with mild DKA are alert and have pH between 7.25 and utilization of glucose and keto acids. Following the initial
7.30 and β-hydroxybutyrate levels of 3 to 4 mmol/L; those with bolus, an intravenous insulin infusion is initiated at a rate of
moderate DKA are alert or slightly drowsy and have pH between 0.1 U/kg/h. A prospective randomized study showed that a
7.0 and 7.24 and β-hydroxybutyrate levels of 4 to 8 mmol/L; and bolus dose is not required if patients are given insulin infusion

at a rate of 0.14 U/kg/h. When a continuous infusion of insu- overcorrected, (2) tissue anoxia from reduced dissociation of
lin is used, 25 U of regular human insulin should be placed in oxygen from hemoglobin when acidosis is rapidly reversed
250 mL of isotonic saline and the first 50 mL of solution (leftward shift of the oxygen dissociation curve), and (3) cere-
flushed through to saturate the tubing before connecting it to bral acidosis resulting from lowering of cerebrospinal fluid pH.
the intravenous line. The insulin infusion should be piggy- It must be emphasized, however, that these considerations are
backed into the fluid line so that the rate of fluid replacement less important when severe acidosis exists. It is therefore recom-
can be changed without altering the insulin delivery rate. If the mended that bicarbonate be administered to diabetic patients
plasma glucose level fails to fall at least 10% in the first hour, a in ketoacidosis if the arterial blood pH is 7.0 or less with care-
repeat loading dose (0.1 or 0.14 U/kg) is recommended. ful monitoring to prevent overcorrection.
Rarely, a patient with insulin resistance is encountered; this One to two ampules of sodium bicarbonate (one ampule
requires doubling the insulin dose every 2 to 4 hours if severe contains 44 mEq/50 mL) should be added to 1 L of 0.45%
hyperglycemia does not improve after the first two doses of saline with 20 mEq KCl or to 400 mL of sterile water with
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insulin and fluid replacement. The insulin dose should be 20 mEq KCl and infused over 1 to 2 hours. (Note: Addition
adjusted with the goal of lowering the glucose concentration by of sodium bicarbonate to 0.9% saline would produce a mark-
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about 50 to 70 mg/dL/h (2.8-3.9 mmol/L). If clinical circum- edly hypertonic solution that could aggravate the hyperosmolar
stances prevent use of insulin infusion, then the insulin can be state already present.) It can be repeated until the arterial pH
given intramuscularly. An initial 0.1 U/kg of regular insulin reaches 7.1, but it should not be given if the pH is 7.1 or greater,
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is given intravenously, and at the same time, the same size dose because additional bicarbonate increases the risk of rebound
is given intramuscularly. Subsequently, regular insulin is given metabolic alkalosis as ketones are metabolized. Alkalosis shifts
intramuscularly hourly at a dose of 0.1 U/kg until the blood potassium from serum into cells, which can precipitate a fatal
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glucose falls to around 250 mg/dL, when the insulin can be cardiac arrhythmia. As noted earlier, serious consideration
given subcutaneously. Insulin therapy, either as a continuous should be given to placement of a central venous catheter when
infusion or as injections given every 1 to 2 hours, should be administering fluids to severely ill patients with cardiovascular
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continued until arterial pH has normalized. Patients who nor- compromise.

mally take long acting basal insulins (insulin glargine or insulin 5. Phosphate. Phosphate replacement is seldom required in treat-
op
detemir or insulin degludec) can be given their usual mainte- ing diabetic ketoacidosis. However, if severe hypophosphate-
nance doses during initial treatment of their diabetic ketoaci- mia of less than 1 mg/dL (<0.35 mmol/L) develops during
dosis. The continuation of their subcutaneous basal insulins insulin therapy, a small amount of phosphate can be replaced
means that lower doses of intravenous insulin will be needed,
y
per hour as the potassium salt. Correction of hypophosphate-

and there will be a smoother transition from intravenous insu- mia helps restore the buffering capacity of the plasma, thereby
lin infusion to the subcutaneous regimen. facilitating renal excretion of hydrogen. It also corrects the
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3. Potassium replacement. Total body potassium loss from poly- impaired oxygen dissociation from hemoglobin by regenerat-
uria and vomiting may be as high as 200 mEq. However, ing 2,3-diphosphoglycerate. However, three randomized stud-
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because of shifts of potassium from cells into the extracellular ies in which phosphate was replaced in only half of a group of
space as a consequence of acidosis, serum potassium is usually patients with diabetic ketoacidosis did not show any apparent
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normal to slightly elevated prior to institution of treatment. As clinical benefit from phosphate administration. Moreover,
the acidosis is corrected, potassium flows back into the cells, attempts to use potassium phosphate as the sole means of
and hypokalemia can develop if potassium replacement is not replacing potassium have led to a number of reported cases of
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instituted. If the patient is not uremic and has an adequate severe hypocalcemia with tetany. To minimize the risk of
urine output, potassium chloride in doses of 10 to 30 mEq/h inducing tetany from too rapid replacement of phosphate, the
should be infused during the second and third hours after average deficit of 40 to 50 mmol of phosphate should be
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beginning therapy. Replacement should be started sooner, if replaced intravenously at a rate no greater than 3 to 4 mmol/h in
the initial serum potassium is inappropriately normal or low, a 60- to 70-kg person. A stock solution (Abbott) provides a
up
and should be delayed, if serum potassium fails to respond to mixture of 1.12 g KH2PO4 and 1.18 g K2HPO4 in a 5-mL
initial therapy and remains above 5 mEq/L, as in cases of renal single-dose vial (this equals 22 mmol of potassium and
insufficiency. Occasionally, a patient may present with a serum 15 mmol of phosphate). One-half of this vial (2.5 mL) should
potassium level less than 3.5 mEq/L, in which case insulin be added to 1 L of either 0.45% saline or 5% dextrose in water.
lic
therapy should be delayed until the potassium level is corrected Two liters of this solution, infused at a rate of 400 mL/h, cor-
to greater than 3.5 mEq/L. An electrocardiogram can be help rects the phosphate deficit at the optimal rate of 3 mmol/h and
in monitoring the patient’s potassium status: high peaked provides 4.4 mEq of potassium per hour. Additional potassium
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T waves are a sign of hyperkalemia, and flattened T waves with should be administered as potassium chloride to provide a total
U waves are a sign of hypokalemia. Foods high in potassium of 10 to 30 mEq of potassium per hour, as noted earlier. If the
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content should be prescribed when the patient has recovered serum phosphate remains below 2.5 mg/dL after this infusion,
sufficiently to take food orally. Tomato juice has 14 mEq of a repeat 5-hour infusion can be given.
potassium per 240 mL, and a medium-sized banana has about 6. Hyperchloremic acidosis during therapy. Because of the
10 mEq. Cooperative patients with only mild ketoacidosis may considerable loss of keto acids in the urine during the initial
receive part or all of their potassium replacement orally. phase of therapy, substrate for subsequent regeneration of
4. Sodium bicarbonate treatment. The use of sodium bicarbon- bicarbonate is lost, and correction of the total bicarbonate defi-
ate in management of diabetic ketoacidosis has been ques- cit is hampered. A portion of the bicarbonate deficit is replaced
tioned because clinical benefit was not demonstrated in one with chloride ions infused in large amounts as saline to correct
prospective randomized trial and because of the following the dehydration. In most patients, as the ketoacidosis clears
potentially harmful consequences: (1) development of hypoka- during insulin replacement, a hyperchloremic, low-bicarbonate
lemia from rapid shift of potassium into cells if the acidosis is pattern emerges with a normal anion gap. This is a relatively

benign condition that reverses itself over the subsequent 12 to Disposition

24 hours once intravenous saline is no longer being adminis-
tered. Using a balanced electrolyte solution with a pH of 7.4 After recovery and stabilization, patients should receive intensive
and 98 mEq/L chloride instead of normal saline (pH ~5.5; detailed instructions about how to avoid this potentially disastrous
chloride 154 mEq/L) has been reported to prevent the hyper- complication of diabetes mellitus. They should be taught to rec-
chloremic acidosis. ognize the early symptoms and signs of ketoacidosis.
Urine ketones or capillary blood β-hydroxybutyrate should be
TRANSITION TO SUBCUTANEOUS measured in patients with signs of infection or in those using an
insulin pump when capillary blood glucose is unexpectedly and
INSULIN REGIMEN persistently high. When heavy ketonuria and glycosuria persist on
several successive examinations, supplemental regular insulin
Once the diabetic ketoacidosis is controlled and the patient is awake
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should be administered, and liquid foods such as lightly salted

and able to eat, subcutaneous insulin therapy can be initiated. Ini-
tomato juice and broth should be ingested to replenish fluids and
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tially, the patient may still have significant tissue insulin resistance
electrolytes. Patients should be instructed to contact the physician
and may require a total daily insulin dose of ~0.6 U/kg. Half of the
if ketonuria persists and, especially, if vomiting develops, or if
total daily dose can be given as long-acting basal insulin and the
appropriate adjustment of the infusion rate on an insulin pump
ie
other half as short-acting insulin premeals. The patient should get

does not correct the hyperglycemia and ketonuria. Table 17–20
injection of the basal insulin and a dose of the rapid-acting insulin
summarizes the guidelines for patients regarding ketone testing
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analog with the first meal and the insulin infusion discontinued an
and what to do with the results. Recurrent episodes of severe dia-
hour later. The overlap of the subcutaneous insulin action and insu-
betic ketoacidosis often indicate poor compliance with the insulin
lin infusion is necessary to prevent relapse of diabetic ketoacidiosis.
regimen, and these patients should receive intensive counseling.
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In patients with preexisting diabetes, giving their basal insulin by

subcutaneous injection at initiation of treatment of diabetic ketoaci-
2. HYPERGLYCEMIC, HYPEROSMOLAR
op
dosis simplifies the transition from intravenous to subcutaneous

regimen. The increased tissue insulin resistance is only present for a STATE
few days at most and as the patient improves the doses of both basal This form of hyperglycemic coma is characterized by severe hyper-
y
and bolus insulins should be reduced to avoid hypoglycemia. In glycemia, hyperosmolality, and dehydration in the absence of sig-
fact, a patient with new diagnosis of type 1 diabetes who still has nificant ketosis. It occurs in patients with mild or occult diabetes
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significant β cell function may not require any basal insulin and and patients are typically middle-aged or elderly. Lethargy and
only very low doses of rapid-acting insulin analogs before meals confusion develop as serum osmolality exceeds 300 mOsm/kg,
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after full recovery from the ketoacidosis. Patients with type 2 diabe- and coma can occur if osmolality exceeds 330 mOsm/kg. Under-
tes and diabetes ketoacidosis due to severe illness may initially lying renal insufficiency or congestive heart failure is common,
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require insulin therapy but can often transition back to oral agents and the presence of either worsens the prognosis. A precipitating
during outpatient follow-up. event such as pneumonia, cerebrovascular accident, myocardial
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infarction, burns, or recent operation can often be identified.

Complications and Prognosis Certain drugs, such as phenytoin, diazoxide, glucocorticoids, and
Low-dose insulin infusion and fluid and electrolyte replacement thiazide diuretics, have been implicated in its development, as
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combined with careful monitoring of patients’ clinical and labora- have procedures associated with glucose loading such as peritoneal
dialysis.
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tory responses to therapy have dramatically reduced the mortality

rates of diabetic ketoacidosis to less than 5%. However, this com-
plication remains a significant risk in the aged who have mortality
lic
rates over 20% and in patients in profound coma in whom treat-

ment has been delayed. Acute myocardial infarction and infarc- TABLE 17–20 Guidelines for treatment of ketones in
tion of the bowel following prolonged hypotension worsen the patients with type 1 diabetes.
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outlook. Prior kidney dysfunction worsens prognosis because the

kidney plays a key role in compensating for pH and electrolyte Check Ketones if Blood Glucose Persistently over 250 mg/dL or if
Nauseated or Vomiting
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abnormalities. Symptomatic cerebral edema occurs primarily in

the pediatric population. Risk factors for development include Blood ketones <1.5 mmol/L Blood ketones >1.5 or urine ketones
severe baseline acidosis, rapid correction of hyperglycemia, and or urine ketones absent or moderate or large
small
excess volume administration in the first 4 hours. Onset of head-
Drink plenty of fluids Call medical team for advise or go
ache or deterioration in mental status during treatment should
Give fast-acting insulin by to urgent care or emergency
lead to consideration of this complication. Intravenous mannitol syringe room
at a dosage of 1 to 2 g/kg given over 15 minutes is the mainstay of Monitor glucose levels Drink plenty of fluids
therapy. Excess crystalloid infusion can precipitate pulmonary Give fast-acting insulin by syringe
Monitor ketone levels
edema. Acute respiratory distress syndrome is a rare complication
of treatment for DKA. Note: Blood ketones <0.6 mmol/L are normal.

Pathogenesis osmolality). Ketosis is usually absent or mild; however, a small

degree of ketonuria may be present if the patient has not been
A partial or relative insulin deficiency may initiate the syndrome
eating because of illness. Acidosis is not a part of the hyperglyce-
by reducing glucose utilization by muscle, fat, and liver, while
mic, hyperosmolar state, but it may be present (often lactic acido-
promoting hyperglucagonemia and increasing hepatic glucose
sis) because of other acute underlying conditions (eg, sepsis, acute
output. The result is hyperglycemia that leads to glycosuria and
renal failure, myocardial infarction). Prerenal azotemia is the rule
osmotic diuresis with obligatory water loss. The presence of even
with blood urea nitrogen frequently over 100 mg/dL.
small amounts of insulin is believed to prevent the development of
The physician must initiate a careful search for the event that
ketosis by inhibiting lipolysis in the adipose stores. Therefore,
precipitated the episode of hyperglycemic, hyperosmolar state if it
even though a low insulin-glucagon ratio promotes ketogenesis in
is not obvious after the initial history and physical examination.
the liver, the limited availability of precursor free fatty acids from
Chest x-rays and cultures of blood, urine, and other body fluids
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the periphery restricts the rate at which ketones are formed. If a

should be obtained to look for occult sources of sepsis. Cardiac
patient is unable to maintain adequate fluid intake because of an
enzymes and serial electrocardiograms can be ordered to look for
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associated acute or chronic illness or has suffered excessive fluid

evidence of silent myocardial infarction.
loss (eg, from burns or therapy with diuretics), marked dehydra-
tion results. As plasma volume contracts, renal insufficiency devel-
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ops; this, then, limits renal glucose excretion and contributes Treatment
markedly to the rise in serum glucose and osmolality. As serum There are some differences in fluid, insulin, and electrolyte
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osmolality exceeds 320 to 330 mOsm/kg, water is drawn out of replacement in this disorder, as compared with diabetic ketoacido-
cerebral neurons, resulting in mental obtundation and coma. sis. However, in common with the treatment of ketoacidotic
patients, careful monitoring of the patient’s clinical and laboratory
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Clinical Features response to therapy is essential.

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A. Symptoms and signs The onset of the hyperglycemic, 1. Fluid replacement. The fluid deficit may be as much as 100
hyperosmolar, nonketotic state may be insidious, preceded for to 200 mL/kg or about 9 L. If circulatory collapse is present,
days or weeks by symptoms of weakness, polyuria, and polydipsia. fluid therapy should be initiated with isotonic saline. In all
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A history of reduced fluid intake is common, whether due to inap- other cases, initial replacement with hypotonic (usually 0.45%)
propriate absence of thirst, gastrointestinal upset, or, in the case of saline is preferable, because these patients are hyperosmolar
with considerable loss of body water and excess solute in the
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elderly or bedridden patients, lack of access to water. A history of

vascular compartment. As much as 4 to 6 L of fluid may be
ingestion of large quantities of sugar-containing fluids, such as soft
required in the first 8 to 10 hours. Careful monitoring of fluid
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drinks or orange juice, can occasionally be obtained; these patients quantity and type, urine output, blood pressure, and pulse is
are usually less hyperosmolar than those in whom fluid intake was essential. Placement of a central venous pressure catheter
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restricted. The absence of toxic features of ketoacidosis may retard should be strongly considered to guide replacement of fluid,
recognition of the syndrome and thus delay institution of therapy especially if the patient is elderly or has underlying renal or
cardiac disease. Because insulin therapy decreases plasma glu-
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until dehydration is profound. Because of this delay in diagnosis,

the hyperglycemia, hyperosmolality, and dehydration in hypergly- cose and therefore serum osmolality, a change to isotonic saline
may be necessary at some time during treatment. Once blood
cemic, hyperosmolar, nonketotic coma is often more severe than
glucose reaches 250 mg/dL, 5% dextrose in 0.45% or 0.9%
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in diabetic ketoacidosis. saline solution should be substituted for the sugar-free fluids.
Physical examination reveals the presence of profound dehy- The rate of dextrose infusion should be adjusted to maintain
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dration (orthostatic fall in blood pressure and rise in pulse, supine glycemic levels of 250 to 300 mg/dL (13.9-16.7 mmol/L) in
tachycardia, or even frank shock, dry mucous membranes, order to reduce the risk of cerebral edema. An important end-
decreased skin turgor). The patient may be lethargic, confused, or point of fluid therapy is to restore urinary output to 50 mL/h
or more. When consciousness returns, oral fluids should be
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comatose. Kussmaul respirations are absent unless the precipitat- encouraged.

ing event for the hyperosmolar state has also led to the develop-
2. Electrolyte replacement. Hyperkalemia is less marked, and
ment of metabolic acidosis (eg, sepsis or myocardial infarction
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much less potassium is lost in the urine during the osmotic

with shock). diuresis of hyperglycemic, hyperosmolar, nonketotic coma
than in diabetic ketoacidosis. There is, therefore, less severe
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B. Laboratory findings Severe hyperglycemia is present, total potassium depletion, and less potassium replacement is
with blood glucose values ranging from 800 to as high as 2400 needed to restore potassium stores to normal. However,
mg/dL (44.4-133.2 mmol/L). In mild cases, where dehydration is because the initial serum potassium usually is not elevated and
less severe, dilutional hyponatremia as well as urinary sodium because it declines rapidly as insulin therapy allows glucose and
losses may reduce serum sodium to about 120 to 125 mEq/L— potassium to enter cells, it is recommended that potassium
this protects, to some extent, against extreme hyperosmolality. replacement be initiated earlier than in ketotic patients: 10 mEq
of potassium chloride can be added to the initial liter of fluid
Once dehydration progresses further, however, serum sodium can administered if the initial serum potassium is not elevated and
exceed 140 mEq/L, producing serum osmolalities of 330 to 440 if the patient is making urine. When serum phosphate falls
mOsm/kg (normal, 280-295 mOsm/kg; see the section Diabetic below 1 mg/dL during insulin therapy, phosphate replacement
Ketoacidosis for a convenient method for estimating serum can be given intravenously with the same precautions as those

outlined for ketoacidotic patients (see earlier). If the patient is the erythrocytes (which lack the enzymes for aerobic oxidation),
awake and cooperative, part or all of the potassium and phos- skeletal muscle, skin, and brain. The chief pathway for removal of
phate replacement can be given orally. lactic acid is by hepatic (and to some degree renal) uptake for
3. Insulin therapy. In general, less insulin is required to reduce conversion first to pyruvate and eventually back to glucose, a pro-
the hyperglycemia of nonketotic patients than is the case for cess that requires oxygen. Lactic acidosis occurs when excess lactic
patients in diabetic ketoacidosis. In fact, fluid replacement
alone can decrease glucose levels considerably. Insulin treat- acid accumulates in the blood. This can be the result of overpro-
ment should therefore be delayed unless the patient has signifi- duction (tissue hypoxia), deficient removal (hepatic failure), or
cant ketonemia (β-hydroxybutyrate >1 mmol/L). Start the both (circulatory collapse). Lactic acidosis is not uncommon in
insulin infusion rate at 0.05 U/kg/h (no need to give bolus) any severely ill patient suffering from cardiac decompensation,
and titrate to lower blood glucose by 50 to 70 mg/dL/h. Once respiratory or hepatic failure, septicemia, or infarction of the
the patient has stabilized and the blood glucose falls to around bowel or extremities. Type A lactic acidosis is associated with tissue
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250 mg/dL, insulin can be given subcutaneously. hypoxia from hypovolemia or endotoxic shock and need not be
associated with hyperglycemia. Type B lactic acidosis is defined as
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Complications and Prognosis that which occurs in the absence of clinical evidence for tissue
The severe dehydration and low output state may predispose the hypoxia and is associated with diabetes per se or with biguanide
patient to complications such as myocardial infarction, stroke,
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therapy.
pulmonary embolism, mesenteric vein thrombosis, and dissemi- With the discontinuance of phenformin therapy in the United
nated intravascular coagulation. Fluid resuscitation remains the
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States, lactic acidosis in patients with diabetes mellitus has become

primary approach to the prevention of these complications. Low- uncommon, but it still must be considered in the acidotic diabetic
dose heparin prophylaxis is reasonable but benefits of routine patient if the patient is seriously ill, and especially if the patient is
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anticoagulation remain doubtful. Rhabdomyolysis is a recognized receiving metformin therapy as well. Most cases of metformin-
complication of the hyperosmolar state, and it should be looked associated lactic acidosis occur in patients in whom there were con-
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for and treated. traindications to the use of metformin, in particular renal failure.
The overall mortality rate of hyperglycemic, hyperosmolar,
nonketotic coma is over 10 times that of diabetic ketoacidosis, Clinical Features
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chiefly because of its higher incidence in older patients, who may A. Symptoms and signs The main clinical features of lactic
have compromised cardiovascular systems or associated major ill- acidosis are marked hyperventilation and mental confusion, which
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nesses. When patients are matched for age, the prognoses of these may progress to stupor or coma. When lactic acidosis is secondary
two forms of hyperosmolar coma are reasonably comparable. to tissue hypoxia or vascular collapse, the clinical presentation is
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When prompt therapy is instituted, the mortality rate can be variable, reflecting that of the prevailing catastrophic illness. In the
reduced from nearly 50% to that related to the severity of coexis- rare instance of idiopathic or spontaneous lactic acidosis, the onset
tent disorders. After the patient is stabilized, the appropriate form
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is rapid (usually over a few hours), the cardiopulmonary status is

of long-term management of the diabetes must be determined. stable, and mentation may be relatively normal.
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Insulin treatment should be continued for a few weeks, but the

patients usually recover sufficient endogenous insulin secretion to B. Laboratory findings Plasma glucose can be low, normal,
make a trial of diet or diet plus oral agents worthwhile. When the or high in diabetic patients with lactic acidosis, but usually it is
moderately elevated. Plasma bicarbonate and arterial pH are quite
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episode occurs in a patient who has known diabetes, then educa-

tion of the patient and caregivers should be instituted. They low. An anion gap is present (calculated by subtracting the sum of
the plasma bicarbonate and chloride from the plasma sodium;
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should be taught how to recognize situations (gastrointestinal

upset, infection) that predispose to recurrence of hyperglycemic, normal is 12-15 mEq/L). Ketones are usually absent from plasma,
hyperosmolar state as well as detailed information on how to pre- but small amounts may be present in urine if the patient has not
been eating recently. Other causes of anion gap metabolic acidosis
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vent the escalating dehydration (small sips of sugar-free liquids,

increase in usual hypoglycemic therapy, or early contact with the should be excluded—for example, uremia, diabetic or alcoholic
physician) that culminates in hyperosmolar coma. ketoacidosis, and salicylate, methanol, ethylene glycol, or paralde-
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hyde intoxication. In the absence of azotemia, hyperphosphatemia

may be a clue to the presence of lactic acidosis.
3. LACTIC ACIDOSIS
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The diagnosis is confirmed by demonstrating, in a sample of

When severely ill diabetic patients present with profound acidosis blood that is promptly chilled and separated, a plasma lactate con-
and an anion gap over 15 mEq/L but relatively low or undetect- centration of 6 mmol/L or higher (normal is ~1 mmol/L). Failure
able levels of keto acids in plasma, the presence of excessive plasma to rapidly chill the sample and separate the plasma can lead to falsely
lactate (>5 mmol/L) should be considered, especially if other high plasma lactate values as a result of continued glycolysis by the
causes of acidosis such as uremia are not present. red blood cells. Frozen plasma remains stable for subsequent assay.
Pathogenesis Treatment
Lactic acid is the end product of the anaerobic metabolism of The cornerstone of therapy is aggressive treatment of the precipi-
glucose. Normally, the principal sources of this acid are tating cause. An adequate airway and good oxygenation should

be ensured. If hypotension is present, fluids and, if appropriate, TABLE 17–21 Chronic complications of diabetes
pressor agents must be given to restore tissue perfusion. Appro- mellitus.
priate cultures and empiric antibiotic coverage should be insti-
Eyes
tuted in any seriously ill patient with lactic acidosis in whom the
Diabetic retinopathy
cause is not immediately apparent. Alkalinization with intrave- Nonproliferative (background)
nous sodium bicarbonate to keep the pH above 7.2 has been Proliferative
recommended in the emergency treatment of severe lactic acido- Cataracts
Subcapsular (snowflake)
sis. However, there is no evidence that the mortality rate is favor- Nuclear (senile)
ably affected by administering bicarbonate, and the matter is at Kidneys
present controversial, particularly because of the hazards associ- Intercapillary glomerulosclerosis
ated with bicarbonate therapy. Hemodialysis may be useful in Diffuse
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Nodular
those cases associated with metformin toxicity. Dichloroacetate, Infection
an anion that facilitates pyruvate removal by activating pyruvate
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Pyelonephritis
dehydrogenase, reverses certain types of lactic acidosis in ani- Perinephric abscess
mals, but in a prospective controlled clinical trial involving 252 Renal papillary necrosis
Renal tubular necrosis
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patients with lactic acidosis, dichloroacetate failed to alter either Following dye studies (urograms, arteriograms)
hemodynamics or survival. Nervous System
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Peripheral neuropathy
Distal, symmetric sensory loss
CHRONIC COMPLICATIONS OF Motor neuropathy
Foot drop, wrist drop
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DIABETES MELLITUS (TABLE 17–21) Cranial nerves III, IV, VI, VII
Diabetic amyotrophy
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In most patients with diabetes, a number of pathologic changes Autonomic neuropathy

Postural hypotension
occur at variable intervals during the course of the disease. These Resting tachycardia
changes involve the vascular system for the most part; however, Loss of sweating
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they also occur in the nerves, the skin, and the lens. In addition to Gastroparesis
these complications, patients with diabetes have an increased inci- Diabetic diarrhea
Urinary bladder atony
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dence of certain types of infections and may handle their infec- Impotence (may also be secondary to pelvic vascular disease)
tions less well than the general population. Skin
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Diabetic dermopathy (shin spots)

Necrobiosis lipoidica diabeticorum
Classifications of Diabetic Vascular Disease Candidiasis
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Foot and leg ulcers

Diabetic vascular disease is conveniently divided into two main Neurotropic
categories: microvascular disease and macrovascular disease.
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Ischemic
Cardiovascular System
Heart disease
A. Microvascular disease Disease of the smallest blood ves- Myocardial infarction
sels, the capillary and the precapillary arterioles, is manifested
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Cardiomyopathy
mainly by thickening of the capillary basement membrane. Micro- Peripheral vascular disease
vascular disease involving the retina leads to diabetic retinopathy, Ischemic ulcers: gangrene
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Cerebrovascular disease
and disease involving the kidney causes diabetic nephropathy. Bones and Joints
Small vessel disease may also involve the heart, and cardiomegaly Diabetic cheiroarthropathy
with heart failure has been described in diabetic patients with pat-
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Dupuytren contracture
ent coronary arteries. Charcot joint
Osteomyelitis
Unusual Infections
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B. Macrovascular disease Large vessel disease in diabetes Necrotizing fasciitis

is essentially an accelerated form of atherosclerosis. It accounts Necrotizing myositis
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Mucor meningitis
for the increased incidence of myocardial infarction, stroke, and Emphysematous cholecystitis
peripheral gangrene in diabetic patients. Just as in the case of Malignant otitis externa
atherosclerosis in the general population, the exact cause of
accelerated atherosclerosis in the diabetic population remains
unclear. Abnormalities in vessel walls, platelets and other com- Prevalence of Chronic Complications by
ponents of the clotting system, red blood cells, and lipid metabo-
lism have all been postulated to play a role. In addition, there is Type of Diabetes
evidence that coexistent risk factors, such as cigarette smoking Although all of the known complications of diabetes can be found
and hypertension, may be important in determining the course in both types of the disease, some are more common in one type
of the disease. than in the other. In type 1 diabetes, end-stage renal disease

develops in up to 40% of patients, compared with less than 20% Inhibitors of the protein kinase β isoform improve retinopathy
of patients with type 2 diabetes. Although blindness occurs in and nephropathy in experimental models.
both types, it occurs more commonly as a result of severe prolif- Hyperglycemia increases hexosamine pathway flux by providing
erative retinopathy, vitreous hemorrhages, and retinal detachment more fructose-6-phosphate for the rate-limiting enzyme of the path-
in type 1 disease, whereas macular edema and ischemia are the way glutamine: fructose-6-phosphate amidotransferase. Activity of
usual cause in type 2 disease. Similarly, although diabetic neuropa- this pathway leads to increased donation of N-acetylglucosamine
thy is common in both type 1 and type 2 diabetes, severe auto- moieties to serine and threonine moieties of complication-
nomic neuropathy with gastroparesis, diabetic diarrhea, resting promoting factors such as PAI-1 or TGF-β.
tachycardia, and postural hypotension is much more common in It has been proposed that all four of these pathways are associ-
type 1. ated with overproduction of superoxide by mitochondria. High
In patients with type 1 diabetes, complications from end-stage ambient glucose leads to increased substrate flux through glycolysis
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renal disease are a major cause of death, whereas patients with type and the tricarboxylic acid cycle. This leads to increased potential
2 diabetes are more likely to have macrovascular diseases leading difference across the inner mitochondrial membrane and generation
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to myocardial infarction and stroke as the main causes of death. of superoxide by the electron transport chain. The increased pro-
Cigarette use adds significantly to the risk of both microvascular duction of superoxide reduces glyceraldehyde-3-phosphate dehy-
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and macrovascular complications in diabetic patients. drogenase (GAPDH) activity, which in turn leads to upstream
increase in intracellular glucose and accumulation of glycolytic
Molecular Mechanisms by Which
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intermediates such as glyceraldehyde-3-phosphate and fructose-

Hyperglycemia Causes Microvascular and 6-phosphate. The increased intracellular glucose leads to increased
flux through the polyol pathway and also is the primary initiating
Macrovascular Damage
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event in the formation of both intracellular and extracellular AGEs.

Epidemiological data and prospective intervention studies such as The glycolytic intermediates are important initiators of the hexos-
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the DCCT have confirmed the central role of glucose in the devel- amine pathway (fructose-6-phosphate) or the protein kinase C
opment of chronic diabetic complications. pathway (glyceraldehyde-3-phosphate).
Four molecular mechanisms of glucose-induced damage have
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been proposed: (1) increased polyol pathway flux; (2) increased

intracellular advanced glycation end product (AGE) formation; Genetic Factors in Susceptibility to
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(3) activation of protein kinase C; and (4) increased hexosamine Development of Chronic Complications of
pathway flux.
Diabetes
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Increase flux through the polyol pathway consumes NADPH.

Because this cofactor is needed to regenerate reduced glutathione, Although no genetic susceptibility genes have been identified as
NADPH depletion is predicted to exacerbate intracellular oxida- yet, two unrelated observations indicate that approximately 40%
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tive stress and cause cellular injury. Inhibitors of aldose reductase, of people with diabetes may be unusually susceptible to the rav-
ages of hyperglycemia or other metabolic sequelae of an inade-
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the first enzyme in the polyol pathway have been shown to

improve diabetic neuropathy. quate insulin effect.
Intracellular autoxidation of glucose results in production of (1) In one retrospective study of 164 juvenile-onset diabetic
patients with a median age at onset of 9 years, 40% were
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intracellular dicarbonyls (glyoxal, 3-deoxyglucosone, methylgly-

oxal), also referred to as AGE precursors. These precursors damage incapacitated or dead from end-stage renal disease with
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target tissues by modifying intracellular and extracellular proteins proliferative retinopathy after a 25-year follow-up, whereas
and matrix components. Intracellular protein modifications may the remaining subjects were either mildly affected (40%) or
alter cellular functions. Modifications of extracellular matrix pro- had no clinically detected microvascular disease (20%). This
lic
teins result in abnormal interactions with other matrix proteins and study was completed long before the availability of glycemic
integrins. The modified plasma proteins bind to receptors on endo- self-monitoring methodology, so it is unlikely that any of
thelial cells, mesangial cells, and macrophages causing expression of these patients were near optimal glycemic control.
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cytokines and growth factors including interleukin 1, IGF-1, TNF- (2) Data from renal transplantation indicate that only about
α, transforming growth factor-β (TGF-β), macrophage colony 40% of normal kidneys developed evidence of moderate to
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stimulating factor, granulocyte-macrophage stimulating factor, severe diabetic nephropathy within 6 to 14 years of being
platelet-derived growth factor, thrombomodulin, tissue factor, vas- transplanted into diabetic subjects with end-stage renal
cular cell adhesion molecule 1 (VCAM 1), and vascular endothelial failure, whereas as many as 60% were only minimally
growth factor (VEGF). Induction of VEGF has been implicated in affected. These observations support the hypothesis that
the vascular hyperpermeability associated with diabetes. although approximately 60% of people suffer only mini-
Protein kinase C isoforms β and δ are activated by diacylglyc- mal consequences from hyperglycemia and other meta-
erol whose levels are increased by elevated intracellular glucose. bolic hazards of insulin insufficiency, 40% or so suffer
Activation of these isoforms leads to alterations in expression of severe, potentially catastrophic microvascular complica-
endothelial nitric oxide synthase, endothelin 1, VEGF, TGF-β, tions if the disease is poorly controlled. The genetic
PAI-1, and activation of nuclear factor κB and NADPH oxidases. mechanisms for this increased susceptibility are as yet

unknown but could be related to one or more of the A. Pathogenesis and clinical features It is now recognized
molecular mechanisms outlined earlier. Identification of that diabetic retinopathy is not only a microvascular complication of
the genetic mechanism(s) would be very helpful in justify- endothelial dysfunction but also a neurodegenerative disease. There is
ing more intensive insulin therapy in the group susceptible thinning of the inner nuclear layer; reduction in synapse numbers
to complications in an effort to achieve near-normalization and synaptic proteins and changes in dendritic morphology.
of blood glucose. The remaining 60% of less susceptible Two main categories of diabetic retinopathy exist: nonprolif-
individuals might then be spared the inconveniences of erative and proliferative. Diabetic macular edema can occur at any
strict glycemic control as well as the risks of hypoglycemia stage but more prevalent in the later phases.
inherent in present methods of intensive insulin therapy. Nonproliferative (background) retinopathy (Figure 17–15)
represents the earliest stage of retinal involvement by diabetes and
SPECIFIC CHRONIC COMPLICATIONS OF
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is characterized by such changes as microaneurysms, dot hemor-

DIABETES MELLITUS (TABLE 17–21) rhages, exudates, and retinal edema. During this stage, the retinal
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capillaries leak proteins, lipids, or red cells into the retina. When
1. OPHTHALMOLOGIC COMPLICATIONS this process occurs in the macula (clinically significant macular
edema), the area of greatest concentration of visual cells, there is
Diabetic Retinopathy
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interference with visual acuity; this is the most common cause of

For early detection of diabetic retinopathy, adolescent or adult visual impairment in type 2 diabetes.
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patients who have had type 1 diabetes for more than 5 years and Proliferative retinopathy (Figure 17–16) involves the growth
all patients with type 2 diabetes should be referred to an ophthal- of new capillaries and fibrous tissue within the retina and into the
mologist for examination and follow-up. In patients with type 1 vitreous chamber. It is a consequence of small vessel occlusion,
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diabetes, after 10 to 15 years, 25% to 50% of patients show some which causes retinal hypoxia; this in turn stimulates new vessel
signs of retinopathy. This prevalence increases to 75% to 95% growth. New vessel formation may occur at the optic disc or else-
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after 15 years and approaches 100% after 30 years of diabetes. In where on the retina. Proliferative retinopathy can occur in both
patients with type 2 diabetes, 60% have nonproliferative retinopa- types of diabetes but is more common in type 1, developing about
thy after 16 years. When hypertension is present in a patient with 7 to 10 years after onset of symptoms, with a prevalence of 25%
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diabetes, it should be treated vigorously because hypertension is after 15 years’ duration. Prior to proliferation of new capillaries, a
associated with an increased incidence and accelerated progression preproliferative phase often occurs in which arteriolar ischemia is
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of diabetic retinopathy. manifested as cotton-wool spots (small infarcted areas of retina).

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at
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FIGURE 17–15 Nonproliferative diabetic retinopathy with intraretinal hemorrhages and microaneurysms along inferotemporal arcade;
and hard exudates temporal to macula. (Used with permission from Dr. Jacque Duncan, University of California, San Francisco.)

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FIGURE 17–16 Proliferative diabetic retinopathy with neovascularization of the disc, venous beading, hemorrhages, and cotton wool
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spots nasal to the optic nerve. Early frame of fluorescein angiogram shows extensive macular capillary nonperfusion and early leakage from
neovascularization along the superotemporal arcade. (Used with permission from Dr. Jacque Duncan, University of California, San Francisco.)
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Vision is usually normal until vitreous hemorrhage or retinal with type 1 diabetes, may come on fairly rapidly, and has a signifi-
detachment occurs. Proliferative retinopathy is a leading cause of cant correlation with the hyperglycemia of uncontrolled diabetes.
blindness in the United States, particularly because it increases the This type of cataract has a flocculent or snowflake appearance and
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risk of retinal detachment. develops just below the lens capsule.

Senile cataract represents a sclerotic change of the lens
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B. Treatment Extensive scatter xenon or argon photocoagula- nucleus. It is by far the most common type of cataract found in
tion and focal treatment of new vessels reduce severe visual loss in either diabetic or nondiabetic adults and tends to occur at a
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those cases in which proliferative retinopathy is associated with younger age in diabetic patients, particularly when glycemic
recent vitreous hemorrhages or in which extensive new vessels are control is poor.
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located on or near the optic disk. Vitreoretinal surgery is used for Two separate abnormalities found in diabetic patients, both of
sight threatening complications of proliferative diabetic retinopa- which are related to elevated blood glucose levels, may contribute
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thy such as vitreous hemorrhage, tractional retinal detachment, to the formation of cataracts: (1) glycosylation of the lens protein,
and epimacular proliferation. and (2) an excess of sorbitol, which is formed from the increased
Macular edema, which is more common than proliferative reti- quantities of glucose found in the insulin-independent lens. Accu-
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nopathy in patients with type 2 diabetes (up to 20% prevalence), mulation of sorbitol leads to osmotic changes in the lens that
has a guarded prognosis, but it has also responded to scatter ultimately result in fibrosis and cataract formation.
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therapy with improvement in visual acuity if detected early. Intra-

vitreal anti-vascular endothelial growth factor (anti-VEGF) agents Glaucoma
(ranibizumab, bevacizumab, pegaptanib, and aflibercept) have
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emerged as new treatments for diabetic macular edema and in Glaucoma occurs in approximately 6% of persons with diabetes.
clinical trials are better than laser therapy in preserving and It is generally responsive to the usual therapy for open-angle dis-
ease. Closed-angle glaucoma can result from neovascularization of
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improving vision. A significant proportion of patients, however,

may still require focal or grid laser treatment. Intravitreal cortico- the iris in diabetic patients, but this is relatively uncommon except
steroids are effective and are used in patients affected by persistent after cataract extraction when accelerated new vessel growth
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or refractory diabetic macular edema, especially in pseudophakic involving the angle of the iris obstructs outflow.
eyes. Avoiding tobacco use and correction of associated hyperten-
sion are important therapeutic measures in the management of 2. RENAL COMPLICATIONS
diabetic retinopathy. There is no contraindication to using aspirin
in patients with proliferative retinopathy. Diabetic Nephropathy
A. Pathogenesis and clinical findings About 4000 cases
Cataracts of end-stage renal disease due to diabetic nephropathy occur
Two types of cataracts occur in diabetic patients: subcapsular and annually among diabetic patients in the United States. This repre-
senile. Subcapsular cataract occurs predominantly in patients sents about one-third of all patients being treated for renal failure.

The cumulative incidence of nephropathy differs between the two syndrome with hypoalbuminemia, edema, and an increase in cir-
major types of diabetes. Patients with type 1 diabetes, who have culating LDL cholesterol as well as progressive azotemia. In con-
not received intensive insulin therapy and have had only fair to trast to all other renal disorders, the proteinuria associated with
poor glycemic control, have a 30% to 40% chance of having diabetic nephropathy does not diminish with progressive renal
nephropathy after 20 years—in contrast to the much lower fre- failure (patients continue to excrete 10-11 g daily as creatinine
quency in patients with type 2 diabetes, who are not receiving clearance diminishes). As renal failure progresses, there is an eleva-
intensive therapy, in whom only about 15% to 20% develop clini- tion in the renal threshold at which glycosuria appears.
cal renal disease. However, because so many more individuals are Patients with diabetic nephropathy should be evaluated and
affected with type 2 diabetes, end-stage renal disease is much more followed by a nephrologist. There has been gradual improvement
prevalent in people with type 2 diabetes in the United States and in quality of life of diabetic patients receiving dialysis but mortal-
especially throughout the rest of the world. There is no question ity remains higher than in nondiabetic patients. During 5 years of
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that improved glycemic control and more effective therapeutic follow-up in a European registry study, the mortality rate in peo-
measures to correct hypertension can reduce the incidence of end- ple with diabetes receiving dialysis was 226.9 deaths/1000 patient
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stage renal disease in both types of diabetes in the future. years whereas the rate was 151.4 deaths/1000 patient years in
Diabetic nephropathy is initially manifested by proteinuria; people receiving dialysis who did not have diabetes.
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subsequently, as kidney function declines, urea and creatinine Renal transplantation, especially from related donors, is often
accumulate in the blood. Thickening of capillary basement mem- successful. For patients with compatible donors and no contrain-
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branes and of the mesangium of renal glomeruli produces varying dications (such as severe cardiovascular disease), it is the treatment
degrees of glomerulosclerosis and renal insufficiency. Diffuse glo- of choice. Diabetic nephropathy accounts for about 20% of kid-
merulosclerosis is more common than nodular intercapillary glo- ney transplantations performed annually in the United States.
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merulosclerosis (Kimmelstiel-Wilson lesions); both produce heavy

proteinuria. Necrotizing Papillitis
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Sensitive radioimmunoassay methods have permitted detection This unusual complication of pyelonephritis occurs primarily in
of microgram concentrations of urinary albumin. Conventional diabetic patients. It is characterized by fever, flank pain, pyuria,
24-hour urine collections, in addition to being inconvenient for and sloughing of renal papillae in the urine. It is treated by intra-
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patients, also show wide variability of albumin excretion, since sev- venous administration of appropriate antibiotics.
eral factors such as sustained erect posture, dietary protein, and
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exercise tend to increase albumin excretion rates. For these reasons,

Renal Decompensation After
an albumin-creatinine ratio in an early morning spot urine collected
Administration of Radiographic Dyes
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upon awakening is preferable. In the early morning spot urine, a

ratio of albumin (μg/L) to creatinine (mg/L) of less than 30 μg/mg The use of radiographic contrast agents in diabetic patients with
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creatinine is normal, and a ratio of 30 to 300 μg/mg creatinine sug- reduced creatinine clearance has been associated with the develop-
gests abnormal microalbuminuria. At least two early morning spot ment of acute renal failure. Contrast-induced nephropathy is
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urine collections over a 3- to 6-month period should be abnormal defined as an increase in serum creatinine of at least 0.5 mg/dL or
before a diagnosis of microalbuminuria is made. 25% compared with baseline after exposure to intravenous con-
Subsequent renal failure can be predicted by persistent urinary trast. The increase in serum creatinine occurs shortly after the
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albumin excretion rates exceeding 30 μg/mg creatinine. Glycemic procedure and peaks 3 to 5 days later before improving over the
control as well as a protein diet of 0.8 g protein/kg body weight/d next 1 to 3 weeks. Although frequently transient, it can cause
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may reduce both the hyperfiltration and the elevated microalbu- permanent impairment of renal function. Diabetic patients with
minuria in patients in the early stages of diabetes and those with normal renal function do not appear to be at increased risk for
incipient diabetic nephropathy. Antihypertensive therapy also contrast nephropathy. If a contrast study is considered essential,
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decreases microalbuminuria. Evidence from some studies—but patients with a serum creatinine of 1.5 to 2.5 mg/dL should be
not the UKPDS—supports a specific role for ACE inhibitors in adequately hydrated before the procedure. Hydration with saline
reducing intraglomerular pressure in addition to lowering sys- has been the cornerstone of contrast nephropathy prevention:
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temic blood pressure. An ACE inhibitor (captopril, 50 mg twice intravenous saline 1 mL/kg/h is started 12 hours before the proce-
daily) in normotensive diabetics impedes progression to protein- dure and continued for 12 hours afterward. Some studies suggest
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uria and prevents the increase in albumin excretion rate. Since that sodium bicarbonate infusions are more effective, and an
microalbuminuria has been shown to correlate with elevated alternate option is to infuse sodium bicarbonate: 150 mL of
nocturnal systolic blood pressure, it is possible that normotensive sodium bicarbonate (1 mEq/mL) is added to 1 L of 5% dextrose
diabetic patients with microalbuminuria have slightly elevated and infused at 3.5 mL/kg/h for 1 hour before the procedure;
systolic blood pressure during sleep, which is lowered during anti- 1.2 mg/kg/h during the procedure and for 6 hours afterward.
hypertensive therapy. This action may contribute to the reported N-acetylcysteine has also been shown in some trials to decrease the
efficacy of ACE inhibitors in reducing microalbuminuria in nor- incidence of contrast nephropathy. One regimen consists of using
motensive patients. oral N-acetylcysteine 600 mg twice a day starting the day before
If treatment is inadequate, then the disease progresses with the procedure for a total of four doses. A combination of
proteinuria of varying severity, occasionally leading to nephrotic N-acetylcysteine and intravenous saline or intravenous sodium

bicarbonate may be more beneficial. Radiographic contrast

material should not be given to a patient with a serum creatinine
greater than 3 mg/dL unless the potential benefit outweighs the
high risk of acute renal failure.
3. NEUROLOGIC COMPLICATIONS

(DIABETIC NEUROPATHY)
Peripheral and autonomic neuropathies are the two most common
complications of both types of diabetes. Up to 50% of patients
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with type 2 diabetes are affected. The pathogenesis of both types

of neuropathy is poorly understood. Some lesions, such as the
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acute cranial nerve palsies and diabetic amyotrophy, have been

attributed to ischemic infarction of the involved peripheral nerve.
The much more common symmetric sensory and motor periph-
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eral neuropathies and autonomic neuropathy are felt to be due to

metabolic complications.
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Unfortunately, there is no consistently effective treatment for FIGURE 17–17 Neuropathic ulceration over first metatarsal
any of the neuropathies. However, several long-term clinical trials head.
have definitively shown that normalization of blood glucose levels
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can prevent development and progression of this devastating

process progresses, there is frank osteoclastic destruction leading
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complication.
to deranged and unstable joints particularly in the midfoot.
Not surprisingly, the key issue for healing of neuropathic ulcers
in a foot with good vascular status is mechanical unloading. Addi-
Peripheral Neuropathy
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tionally, any infection should be treated with debridement and

A. Distal symmetric polyneuropathy This is the most appropriate antibiotics. Healing times of 8 to 10 weeks are typical.
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common form of diabetic peripheral neuropathy in which loss of In the occasional patient, where healing appears refractory, platelet-
function appears in a stocking-glove pattern and is due to an axo- derived growth factor (becaplermin) should be considered for
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nal neuropathic process. Longer nerves are especially vulnerable— local application. A postmarket epidemiologic study showed
hence the impact on the foot. Both motor and sensory nerve increased cancer deaths in patients who had used three or more
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conduction is delayed in the peripheral nerves, and ankle jerks tubes of becaplermin on their leg or feet ulcers, and there is now
may be absent. a boxed warning in the drug label. Once ulcers are healed, thera-
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Sensory involvement usually occurs first and is generally bilat- peutic footwear is key to preventing recurrences. Custom-molded
eral, symmetric, and associated with dulled perception of vibra- shoes are reserved for patients with significant foot deformities.
tion, and temperature. Pain, when present, can range from mild Other patients with neuropathy may require accommodative
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discomfort to severe incapacitating symptoms (discussed later). insoles that distribute the load over as wide an area as possible.
The sensory deficit may eventually be of sufficient degree to pre- Patients with foot deformities and loss of protective threshold
up
vent patients from feeling pain. Patients with symptoms of sensory should seek regular care from a podiatrist. They should be edu-
neuropathy should be examined with a 5.07 Semmes-Weinstein cated about appropriate footwear, and those patients with loss of
filament. Those who cannot feel the filament must be considered protective threshold should be instructed to inspect their feet daily
lic
at risk for unperceived neuropathic injury. for reddened areas, blisters, abrasions, or lacerations.
The denervation of the small muscles of the foot results in In some patients, hypersensitivity to light touch and occasion-
clawing of the toes and displacement of the submetatarsal fat pads ally severe burning pain, particularly at night, can become physi-
at
anteriorly. These changes, together with the joint and connective cally and emotionally disabling. Nortriptyline or desipramine in
tissue changes, alter the biomechanics of the foot, increasing plan- doses of 25 to 150 mg/d orally may provide dramatic relief for
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tar pressures. This combination of decreased pain threshold, pain from diabetic neuropathy, often within 48 to 72 hours. This
abnormally high foot pressures, and repetitive stress (eg, walking) rapid response is in contrast to the 2 or 3 weeks required for an
can lead to calluses and ulcerations in the high-pressure areas such antidepressive effect. Patients often attribute the benefit to having
as over the metatarsal heads (Figure 17-17). Peripheral neuropathy a full night’s sleep. Mild to moderate morning drowsiness is a
also predisposes to the development of Charcot arthropathy. side effect that generally improves with time or can be lessened by
Other predisposing factors for this condition include autonomic giving the medication several hours before bedtime. This medica-
neuropathy and trauma. The acute Charcot foot presents with tion should not be continued if improvement has not occurred
pain and swelling, and if the condition is untreated, it leads to a after 5 days of therapy. Amitriptyline, 25 to 75 mg orally at
rocker bottom deformity and ulceration. The early radiologic bedtime can also be used but has more anticholinergic effects.
changes are of joint subluxation and periarticular fractures. As the Tricyclic antidepressants, in combination with the phenothiazine,

fluphenazine, have been shown in two studies to be efficacious in Autonomic Neuropathy

painful neuropathy, with benefits unrelated to relief of
Neuropathy of the autonomic nervous system is common in
depression.
patients with diabetes of long duration and can be a very discon-
Gabapentin (900-1800 mg/d in three divided doses) has also
certing clinical problem. It can affect many diverse visceral func-
been shown to be effective in the treatment of painful neuropathy
tions including blood pressure and pulse, gastrointestinal activity,
and should be tried if the tricyclic drugs prove ineffective. Prega-
bladder function, and erectile function. Treatment is directed
balin, a congener of gabapentin, has been shown in an 8-week
specifically at each abnormality.
study to be more effective than placebo in treating painful diabetic
Involvement of the gastrointestinal system may be manifested
peripheral neuropathy. However, this drug was not compared with
by nausea, vomiting, and postprandial fullness (from gastric
an active control. Also, because of its abuse potential, it has been
atony); symptoms of reflux or dysphagia (from esophageal
categorized as a Schedule V controlled substance. Duloxetine
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involvement); constipation and recurrent diarrhea, especially at

(60-120 mg), a serotonin and norepinephrine reuptake inhibitor,
night (from involvement of the small bowel and colon); and fecal
has been approved for the treatment of painful diabetic neuropa-
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incontinence (from anal sphincter dysfunction). Gall bladder

thy. In clinical trials, this drug reduced the pain sensitivity score
function is altered, and this enhances stone formation.
by 40% to 50%. Capsaicin, a topical irritant, has been found to
Gastroparesis should be considered in type 1 diabetic patients
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be effective in reducing local nerve pain; it is dispensed as a cream

in whom unexpected fluctuations and variability in their blood
(Zostrix 0.025% and Zostrix-HP 0.075%) to be rubbed into the
glucose levels develops after meals. Radiographic studies of the
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skin over the painful region two to four times daily. Gloves should
stomach and radioisotopic examination of gastric emptying after
be used for application, because hand contamination could result
liquid and solid meals are of diagnostic value in these patients.
in discomfort if the cream comes in contact with eyes or sensitive
Metoclopramide has been of some help in treating diabetic gastro-
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areas such as the genitalia. Five percent lidocaine patch applied

paresis. It is a dopamine antagonist that has central antiemetic
over an area of maximal pain has been reported to be of benefit.
effects as well as a cholinergic action to facilitate gastric emptying.
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Rapid normalization of glucose levels in a patient with long

It is given in a dose of 10 mg orally three or four times a day, 30
standing poor control can precipitate an acute painful neuropathy
minutes before meals and at bedtime. Drowsiness, restlessness,
(also called “insulin neuritis” or “treatment induced neuropathy”).
fatigue, and lassitude are common adverse effects. Tardive dyski-
y
Autonomic dysfunction may also be present. The symptoms

nesia and extrapyramidal effects can occur especially when the
improve with time. The initial report of this condition noted that
drug is used for longer than 3 months and the FDA has cautioned
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stopping the insulin treatment resolved the symptoms. There is,

against its chronic use. Domperidone is also a dopamine antago-
however, no conclusive evidence that deliberately raising glucose
nist and as effective as metoclopramide but with less central side
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levels will ameliorate the symptoms. Treatment induced neuropa-

effects. The dose is 10 to 20 mg three or four times a day. It can
thy can probably be avoided by lowering glucose levels gradually.
cause prolongation of the QT interval and a baseline ECG and
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Diabetic neuropathic cachexia is a syndrome characterized

follow-up ECG should be performed. The drug is not licensed for
by a symmetric peripheral neuropathy associated with profound
sale in the United States but the FDA will allow its use through
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weight loss (up to 60% of total body weight) and painful dyses-
the “expanded access to investigational drugs program.” Erythro-
thesias affecting the proximal lower limbs, the hands, or the
mycin appears to bind to motilin receptors in the stomach and has
lower trunk. Treatment is usually with insulin and analgesics.
been found to improve gastric emptying in doses of 250 mg three
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The prognosis is usually good, and patients typically recover

times daily over the short term, but its effectiveness seems to
their baseline weight with resolution of the painful sensory
diminish over time. Gastric electrical stimulation has been
up
symptoms within 1 year.

reported to improve symptoms and quality of life indices in
B. Isolated peripheral neuropathy Involvement of the patients with gastroparesis refractory to pharmacologic therapy.
Diarrhea associated with autonomic neuropathy has occasion-
lic
distribution of only one nerve (mononeuropathy) or of several

nerves (mononeuropathy multiplex) is characterized by sudden ally responded to broad-spectrum antibiotic therapy (such as
onset with subsequent recovery of all or most of the function. This rifaximin, metronidazole, amoxicillin/clavulanate, ciprofloxacin,
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neuropathology has been attributed to vascular ischemia or trau- or doxycycline), although it often undergoes spontaneous remis-
matic damage. Cranial and femoral nerves are commonly involved, sion. Refractory diabetic diarrhea is often associated with impaired
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and motor abnormalities predominate. The patient with cranial sphincter control and fecal incontinence. Therapy with loper-
nerve involvement usually presents with diplopia. Clinical exami- amide, 4 to 8 mg daily, or diphenoxylate with atropine, two tablets
nation reveals signs of single third, fourth, or sixth nerve weakness, up to four times a day, may provide relief. In more severe cases,
and the pupil is spared. A full recovery of function occurs in 6 to tincture of paregoric or codeine (60-mg tablets) may be required
12 weeks. Diabetic amyotrophy presents with onset of severe pain to reduce the frequency of diarrhea and improve the consistency
in the front of the thigh. Within a few days or weeks of the onset of the stools. Clonidine has been reported to lessen diabetic diar-
of pain, the patient develops weakness and wasting of the quadri- rhea; however, its usefulness is limited by its tendency to cause
ceps. Usually as the weakness appears, the pain tends to improve. orthostatic hypotension in these patients who already have auto-
Management includes analgesia and improved diabetic control. nomic neuropathy. Constipation usually responds to stimulant
The symptoms improve over 6 to 18 months. laxatives such as senna. Metamucil and other bulk-providing

agents may relieve either the diarrhea or the constipation phases, or hypertension, and men who have a history of cardiac failure or
which often alternate. have unstable angina. Rarely, a decrease in vision or permanent
Inability to completely empty the bladder can sometimes occur. visual loss has been reported after PDE5 inhibitor use.
Bethanechol in doses of 10 to 50 mg three times a day has occasion- Intracorporeal injection of vasoactive drugs causes penile
ally improved emptying of the atonic urinary bladder. Catheter engorgement and erection. Drugs most commonly used include
decompression of the distended bladder has been reported to papaverine alone, papaverine with phentolamine, and alprostadil
improve its function, and considerable benefit has been reported (prostaglandin E1). Alprostadil injections are relatively painless,
after surgical severing of the internal vesicle sphincter. but careful instruction is essential to prevent local trauma, pria-
Use of Jobst fitted stockings, tilting the head of the bed, and pism, and fibrosis. Intraurethral pellets of alprostadil avoid the
arising slowly from the supine position are useful in minimizing problem of injection of the drug.
symptoms of orthostatic hypotension. Some patients may require External vacuum therapy (Erec-Aid System) is a nonsurgical treat-
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the addition of a mineralocorticoid such as fludrocortisone acetate ment consisting of a suction chamber operated by a hand pump that
(0.1-0.2 mg twice daily). Fludrocortisone therapy, however, can creates a vacuum around the penis. This draws blood into the penis
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result in supine hypertension and hypokalemia. Midodrine (10 mg to produce an erection that is maintained by a specially designed ten-
three times a day), an alpha adrenergic agonist, can be tried if sion ring inserted around the base of the penis and which can be kept
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Jobst stockings and sleeping upright prove ineffective in providing in place for up to 20 to 30 minutes. Although this method is generally
symptomatic relief. effective, its cumbersome nature limits its appeal.
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Erectile dysfunction due to neuropathy differs from the psy- Surgical implants of penile prostheses remain an option for those
chogenic variety in that the latter may be intermittent (erections patients in whom the nonsurgical approaches are ineffective.
occur under special circumstances), whereas diabetic erectile dys-
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function is usually persistent. To distinguish neuropathic or psy- 4. CARDIOVASCULAR COMPLICATIONS

chogenic erectile dysfunction from the erectile dysfunction caused
Heart Disease
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by aortoiliac occlusive disease or vasculopathy, papaverine is

injected into the corpus cavernosum of the penis. If the blood Microangiopathy occurs in the heart and may explain the exis-
supply is competent, a penile erection occurs (see Chapter 12). tence of congestive cardiomyopathies found in diabetic patients
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Urinary incontinence, with large volumes of residual urine, and without demonstrable coronary artery disease. Much more com-
retrograde ejaculation can also result from pelvic neuropathy. monly, however, heart failure in patients with diabetes is a conse-
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There are medical, mechanical, and surgical approaches avail- quence of coronary atherosclerosis. Myocardial infarction is three
able for treatment of erectile dysfunction. Penile erection depends to five times more common in diabetic patients than in age-
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on relaxation of the smooth muscle in the arteries of the corpus matched controls and is the leading cause of death in patients with
cavernosum, and this is mediated by nitric oxide-induced cyclic type 2 diabetes. Cardiovascular disease risk is increased in patients
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3′,5′-guanosine monophosphate (cGMP) formation. cGMP- with type 1 diabetes as well, although the absolute risk is lower
specific phosphodiesterase type 5 (PDE5) inhibitors impair the than in patients with type 2 diabetes. Women with diabetes lose
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breakdown of cGMP and improve the ability to attain and main- the protection against myocardial infarction that is usually present
tain an erection. Sildenafil (Viagra), vardenafil (Levitra), and during the childbearing years. The increased risk of atherosclerosis
tadalafil (Cialis) have been shown in placebo-controlled clinical in people with diabetes may reflect the combination of hyperlip-
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trials to improve erections in response to sexual stimulation. The idemia, abnormalities of platelet adhesiveness, coagulation factors,
recommended dose of sildenafil for most patients is one 50-mg hypertension, and oxidative stress and inflammation.
up
tablet taken approximately 1 hour before sexual activity. The peak Large intervention studies of risk factor reduction in diabetes
effect is at 1.5 to 2 hours, with some effect persisting for 4 hours. are lacking, but it is reasonable to assume that reducing these risk
Patients with diabetes mellitus using sildenafil reported 50% to factors would have beneficial effects. Lowering LDL cholesterol
lic
60% improvement in erectile function. The maximum recom- reduces first events in patients without known coronary disease
mended dose is 100 mg. The recommended dose of both varde- and secondary events in patients with known coronary disease.
nafil and tadalafil is 10 mg. The doses may be increased to 20 mg These intervention studies included some patients with diabetes,
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or decreased to 5 mg based on efficacy and side effects. Tadalafil and the benefits of lowering LDL cholesterol were apparent in this
has been shown to improve erectile function for up to 36 hours group. The National Cholesterol Education Program clinical prac-
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after dosing. In clinical trials, only a few adverse effects have been tice guidelines have designated diabetes as a coronary risk equiva-
reported—transient mild headache, flushing, dyspepsia, and, in lent and have recommended that patients with diabetes should
some, altered color vision. Priapism can occur with these drugs have an LDL cholesterol goal of less than 100 mg/dL. Lowering
and patients should be advised to seek immediate medical atten- LDL cholesterol to 70 mg/dL may have additional benefit and is
tion if an erection persists for longer than 4 hours. The PDE5 a reasonable target for most patients with type 2 diabetes who have
inhibitors potentiate the hypotensive effects of nitrates, and their multiple risk factors for cardiovascular disease. In people with
use is contraindicated in patients who are concurrently using diabetes, the association of blood pressure with microvascular and
organic nitrates in any form. Caution is advised for men who have macrovascular events is a continuum. The UKPDS reported that
suffered a heart attack, stroke, or life-threatening arrhythmia a 10 mm Hg decrease in mean systolic pressure was associated
within the previous 6 months; men who have resting hypotension with a risk reduction of 11% for myocardial infarction; 13% for

microvascular complication; and 15% for deaths related to diabe- retinopathy. There was no statistically significant difference in the
tes. There was no threshold of risk for any endpoint and the lowest severity of vitreous/preretinal hemorrhages or their rate of resolution
risk was in those patients whose systolic pressure was less than 120 between the aspirin and placebo groups. Thus, it appears that there
mm Hg. Meta-analyses of clinical trials that included patients is no contraindication to aspirin use to achieve cardiovascular benefit
with diabetes report that if baseline systolic pressure is greater than in diabetic patients who have proliferative retinopathy.
140, treatment to decrease blood pressure toward the normal
range reduces risk of mortality and macrovascular and microvas- Peripheral Vascular Disease
cular events. The data on treatment when baseline systolic pres- Atherosclerosis is markedly accelerated in the larger arteries. It is
sure is less than 140 is conflicting. One meta-analysis found that often diffuse, with localized enhancement in certain areas of tur-
treating patients with baseline systolic pressure less than 140 was bulent blood flow, such as at the bifurcation of the aorta or other
associated with a reduced risk of stroke and albuminuria. Another
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large vessels. Clinical manifestations of peripheral vascular disease

meta-analysis, however, found that if baseline systolic blood pres- include ischemia of the lower extremities, impotence, and intesti-
sure was less than 140, further treatment increased the risk of
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nal angina.
cardiovascular mortality. These meta-analyses included studies of The incidence of gangrene of the feet in people with diabetes
diabetic patients with known cardiovascular disease, chronic renal is 30 times that in age-matched controls. The factors responsible
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failure, heart failure; and stroke and it is possible that including for the development of this condition, in addition to peripheral
these very high-risk patients attenuated or even worsened out- vascular disease, are small vessel disease, peripheral neuropathy
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comes from blood pressure treatment. with loss of both pain sensation and neurogenic inflammatory
The antihypertensive regimen used does not seem to be that responses, and secondary infection. In two-thirds of patients with
important. The key exception is heart failure where diuretics seem ischemic gangrene, pedal pulses are not palpable. In the remaining
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to beneficial. Dual renin-angiotensin blockade with a renin one-third who has palpable pulses, reduced blood flow through
blocker, such as aliskiren, with ACE-inhibition or ARB blockade these vessels can be demonstrated by plethysmographic or Dop-
op
is not recommended because of increased risk of hyperkalema, pler ultrasound examination. Prevention of foot injury is impera-
hypotension and stroke. Similarly, combining an ARB and ACE tive. Agents that reduce peripheral blood flow such as tobacco and
inhibitor has also failed to show benefit and is associated with propranolol should be avoided. Control of other risk factors such
y
hypotension and renal dysfunction. Although evidence that ACE as hypertension is essential. Cholesterol-lowering agents are useful
inhibitors or ARB are of particular benefit is sparse, these classes as adjunctive therapy when early ischemic signs are detected and
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of drugs are well tolerated and are recommended as the first line when dyslipidemia is present. Patients should be advised to seek
antihypertensive treatment in patients with diabetes. immediate medical care if a diabetic foot ulcer develops. Improve-
o
The ADA recommends lowering systolic blood pressure to less ment in peripheral blood flow with endarterectomy and bypass
than 140 mm Hg and diastolic pressure to less than 90 mm Hg in operations is possible in certain patients.
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people with diabetes. The systolic target of 130 mm Hg or less and

diastolic of 80 mm Hg or less is recommended for the younger 5. SKIN AND MUCOUS MEMBRANE
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patient if it can be achieved without undue treatment burden. The

Systolic Blood Pressure Intervention Trial (SPRINT) reported that COMPLICATIONS
treating to a systolic blood pressure of less than 120 mm Hg Chronic pyogenic infections of the skin may occur, especially in
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reduced cardiovascular events by 25% and death from cardiovas- poorly controlled diabetic patients. Candidal infection can produce
cular causes by 43% during 3.26 years of follow-up. People with erythema and edema of intertriginous areas below the breasts, in the
up
diabetes, however, were excluded from this study and it is unclear axillas, and between the fingers. It causes vulvovaginitis in most
if the results are applicable to this population. chronically uncontrolled diabetic women with persistent glucosuria
Aspirin (81-325 mg daily) inhibits thromboxane synthesis by and is a frequent cause of pruritus. While antifungal creams con-
lic
platelets and is effective in reducing cardiovascular morbidity and taining miconazole or clotrimazole offer immediate relief of vulvo-
mortality in patients who have a history of myocardial infarction or vaginitis, recurrence is frequent unless glucosuria is reduced.
stroke (secondary prevention). It is unclear if aspirin prevents pri- In some patients with type 2 diabetes, poor glycemic control
at
mary cardiovascular events in people with diabetes. The current can cause a severe hypertriglycemia, which can present as eruptive
recommendation is to give aspirin to those people with diabetes who cutaneous xanthomas and pancreatitis. The skin lesions appear as
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are at increased risk for cardiovascular events (>10% 10-year risk of yellow morbilliform eruptions 2 to 5 mm in diameter with ery-
cardiovascular events). Typically this includes most 50-year-old men thematous areolae. They occur on extensor surfaces (elbows,
and 60-year-old women with one or more additional risk factors knees, buttocks) and disappear after triglyceride levels are reduced.
(smoking, hypertension, dyslipidemia, family history of premature Necrobiosis lipoidica diabeticorum (Figure 17-18) are oval or
cardiovascular disease, and albuminuria). Contraindications for aspi- irregularly shaped plaques with reddish demarcated borders and a
rin therapy include age less than 21 years (because of risk of Reye glistening yellowish surface usually located over the anterior sur-
syndrome), aspirin allergy, bleeding tendency (eg, anticoagulant faces of the legs or the dorsal surfaces of the ankles. Rarely, lesions
therapy), recent gastrointestinal bleeding, or active hepatic can occur on the hands, fingers, forearms, face, and scalp. The
disease. The Early Treatment Diabetic Retinopathy Study (ETDRS) necrobiosis lesion usually starts out as an oval violaceous patch
showed that aspirin does not influence the course of proliferative that slowly expands. The advancing border is red and the central

Diabetic cheiroarthropathy is a syndrome of chronic progres-

sive stiffness of the hand secondary to contracture and tightening
of the skin over the joints. It is characterized by inability to flatten
the palms against a flat surface (prayer sign). It is believed to be
due to glycosylation of collagen and perhaps other proteins in con-
nective tissue. It is associated with poor glycemic control and with
longer duration of diabetes.
Dupuytren contractures consist of nodular thickening and
contracture of the palmar fascia of the hand, producing flexure
contractures of the fingers. It can occur in the absence of diabetes,
but is more common in people with diabetes. The etiology is
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unclear but there may be an inflammatory component. Glucocor-

ticoid injection into discrete nodules can sometimes help but the
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standard treatment is surgical fasciectomy.

Carpal tunnel syndrome occurs when the median nerve is
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compressed within the carpal tunnel. It is more common in people

with diabetes, especially those who also have diabetic cheiroar-
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thropathy. It is presumably due to glycosylation of collagen and

other proteins in the connective tissue.
Patients with adhesive capsulitis of the shoulder (frozen shoul-
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der) complain primarily of stiffness and loss of range of motion.

They may also have shoulder pain. It occurs more frequently in
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people with long-standing diabetes—the incidence being two to

four times higher than in the general population. The patients
may also have diabetic cheiroarthropathy or Dupuytren contrac-
y
tures. In most cases it is a limited condition that responds to

physical therapy. Patients should be warned that recovery may take
FIGURE 17–18 Necrobiosis lipoidica diabeticorum.
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6 to 18 months. For a few patients surgery may be necessary.

Adhesive capsulitis of the hip has also been described.
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Data on bone mineral density and fracture risk in people with

area turns yellow-brown. The thinning of the dermis in the center
diabetes are contradictory. Bone mineral density has been reported
of the lesion leads to the shiny surface and prominent telangiecta-
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to be low, normal, or high in type 2 diabetes patients. Type 2

sia. It also allows the subcutaneous fat to become more visible
diabetes patients do appear to be at increased risk for nonvertebral
hence the yellowish appearance. Pathologically, the lesions show
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factures. Women with type 1 diabetes have an increased risk of

degeneration of collagen, granulomatous inflammation of subcu-
fracture when compared to women without diabetes. It is likely
taneous tissues and blood vessels, capillary basement membrane
that other factors such as duration of diabetes and diabetes com-
thickening, and obliteration of vessel lumina. The condition is
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plications such as neuropathy and renal disease affect both the

associated with type 1 diabetes, although it can occur in patients
bone mineral density and fracture risk.
with type 2 diabetes and also in people without diabetes. It occurs
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Diffuse idiopathic skeletal hyperostosis (DISH) is a skeletal

in about 0.3% of patients with diabetes, usually in patients in
disease characterized by ossification of the anterior longitudinal
their 30s and 40s, and is about three times more common in women
ligament of the spine and various extraspinal ligaments. It causes
than in men. In some studies an association with microalbumin-
lic
stiffness and decreased range of spinal motion. The peripheral

uria and retinopathy has been reported. Improving glycemic con-
joints most commonly affected are the metacarpophalangeal
trol may help the condition. The first-line treatment includes
joints, elbows, and shoulders. Diabetes, obesity, hypertension, and
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topical and subcutaneous corticosteroids. Second-line treatments

dyslipidemia are risk factors for this condition.
include systemic steroids, cyclosporine, ticlodipine, nicotinamide,
Hyperuricemia and gout are disorders associated with the meta-
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clofazimine, fumarate esters, intralesional etanercept, and topical

bolic syndrome. Thus, it is not surprising that type 2 diabetes patients
psoralen with ultraviolet A radiation. Pulsed dye lasers can
are at increased risk for acute gout as well as chronic tophaceous gout.
improve the appearance of telangiectasias. Flare-ups are frequent.
Bursitis, particularly of the shoulders and hips, occurs more
No treatment is completely effective.
frequently than expected in patients with diabetes.
Shin spots are uncommon in adult diabetics. They are brownish,
rounded, painless atrophic lesions of the skin in the pretibial area.
7. INFECTION
6. BONE AND JOINT COMPLICATIONS There are also several unusual infections that occur almost exclu-
Bone and joint complications are generally attributed to metabolic sively in diabetic patients (eg, emphysematous cholecystitis,
or vascular sequelae of long-standing diabetes. mucormycosis, malignant otitis externa, and necrotizing

papillitis). As noted earlier, atherosclerosis with peripheral vascular disturbed by the procedure. If this occurs, small amounts of short-
disease is very common in the diabetic population, and the resul- acting insulin, as needed, will correct the hyperglycemia. Patients
tant ischemia undoubtedly plays a role in the frequent and severe on oral agents should not take them on the day of surgery. If there
lower extremity infections seen in these patients. is significant hyperglycemia, short-acting insulin can be given as
needed. If this approach does not provide adequate control, an
insulin infusion should be started in the manner indicated later.
MANAGEMENT OF DIABETES IN THE The oral agents can be restarted once the patient is eating nor-
HOSPITALIZED PATIENT mally after the operation. It is important to order a postoperative
serum creatinine level to ensure normal renal function prior to
A number of studies have observed that hospitalized patients with restarting metformin therapy.
diabetes and those with new-onset hyperglycemia (ie, those with- Patients taking insulin represent the only serious challenge to
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out a preadmission diagnosis of diabetes) have higher inpatient management of diabetes when surgery is necessary. The insulin
morbidity and mortality. The morbidity and mortality in diabetics regimen used to control the glucose depends on the kind of
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is twice that of nondiabetics. Those with new-onset hyperglycemia diabetes (type 1 or type 2); whether it is minor surgery (<2 hours
have even a higher mortality—almost eightfold greater in one and patient eating afterward) or major surgery (longer than 2 hours,
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study. These observations have led to increased interest in improv- invasion of body cavity, not eating afterward); and the preopera-
ing glucose control in the hospitalized diabetic patient. tive insulin regimen (eg, basal bolus or premixed insulin twice a
Most patients with diabetes are hospitalized for reasons other
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day or premeal bolus only or regular before meals and NPH at

than their diabetes. Up to 10% to 15% of all hospitalized patients bedtime). Type 1 patients have to be on some insulin to prevent
have diabetes. Audits suggest that as many as a 30% of hospitalized the development of diabetic ketoacidosis. Many type 2 patients
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diabetic patients have inappropriate management of their diabetes on insulin are fine without insulin for a few hours. Ideally
such as being given metformin where contraindicated, failure to act patients with diabetes should undergo surgery early in the morn-
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on high blood glucose levels, omission of diabetes medication, no ing. Table 17–22 summarizes the approach for these various
record of diabetes complications, inappropriate insulin manage- kinds of patients. One insulin infusion method adds 10 U of
ment, or infrequent blood glucose monitoring. Use of outpatient regular insulin to 1 L of 5% dextrose in half-normal saline, and
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oral therapies or insulin regimens in the hospital is challenging. this is infused intravenously at a rate of 100 to 180 mL/h. This
Patients are not eating according to their normal schedule and are gives the patient 1 to 1.8 U of insulin per hour, which, except in
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often fasting for procedures. It is, therefore, usual to use insulin, the most severe cases, generally keeps the blood glucose within
subcutaneous or intravenous, in the hospitalized patient. Insulin is the range of 100 to 250 mg/dL (5.5-13.9 mmol/L). The infusion
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safe to use in patients with cardiac, renal, and liver disease and its may be continued for several days if necessary. Plasma glucose or
dosing can be adjusted to match changing inpatient needs. blood glucose should be determined every 2 to 4 hours to be sure
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Surgery represents a stressful situation during which most of metabolic control is adequate. If it is not, adjustments in the
the insulin antagonists (catecholamines, GH, corticosteroids) are ratio of insulin to dextrose in the intravenous solution can be
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mobilized. In the patient with diabetes, this can lead to a worsen- made.
ing of hyperglycemia and perhaps even ketoacidosis. The aim of An alternative method, which is gaining increasing popularity,
medical management of people with diabetes during the periop- consists of separate infusions of insulin and glucose delivered by
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erative period is to minimize these stress-induced changes. Recom- pumps to permit independent adjustments of each infusion rate,
mendations for management depend both on the patient’s usual depending on hourly variation of blood glucose values. There are
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diabetic regimen and on the type of surgery (major or minor) to a number of different algorithms available for insulin infusions.
be done. Table 17–23 provides guidelines for management with an insulin
For people with diabetes controlled with diet alone, no spe- infusion and an algorithm designed to achieve glycemic control in
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cial precautions are necessary unless diabetic control is markedly the range of 120 to 180 mg/dL blood glucose.
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TABLE 17–22 Recommendations for management of insulin-treated diabetes during surgery.

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Major Surgical Procedures

Minor Surgical Procedures (>2 h; Invasion of Body Cavity; Not
(2 h; Eating Afterward) Eating Immediately After Recovery)
Type 2 patients on basal bolus No insulin on the day of operation. Start 5% dextrose infusion; Same regimen as minor procedure. If
insulin regimen; twice daily monitor fingerstix blood glucose and give subcutaneous control is not satisfactory, then
premixed insulin short-acting insulin every 4 or 6 h intravenous insulin infusion
Type 1 patient on basal bolus Patients on pump should discontinue the pump the evening Initiate insulin infusion on morning of
insulin regimen or on insulin before procedure and should be given 24 h basal insulin. On procedure and transition back to usual
pump day of procedure, start 5% dextrose; monitor blood glucose regimen when eating
and give subcutaneous short-acting insulin every 4 or 6 h

TABLE 17–23 Guideline for perioperative diabetes management with an intravenous insulin infusion.
1. Maintenance of IV fluids (IV dextrose infusion must be maintained while the patient is on insulin infusion. Minimum rate of 10 mL/h)
□ D5 NS at 100 mL/h
□ D5 1/2 NS at 100 mL/h
□ D10 NS at _________ mL/h (for patients with fluid restrictions or renal failure)
□ Additive: KCl 20 mEq/L (generally 20 mEq/L)
□ Other_________ at _____________ mL/h
2. Regular insulin infusion 100 U regular insulin in 100 mL NS (1 U = 1 mL)
A. Flush first 20 mL of infusion through tubing before connecting to patient
B. Before beginning infusion, check blood glucose (BG) with glucose meter
3. Start insulin infusion rate as follows (when BG ≥100 mg/dL)
□ 0.3 U/h taking <30 U insulin daily (recommended for type 1; Pancreatectomy)
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□ 1 U/h for patients previously diet controlled, taking oral hypoglycemic agent, or <30 U insulin daily
□ 1.5 U/h for patients taking >30 U insulin daily
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□ Other ________ U/h

4. Adjust insulin infusion rate as follows:
□ Standard adjustment □ Sensitive Adjustment (for Type 1; Pancreatectomy)
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BG <80 mg/dL; stop infusion and call MD; BG <80 mg/dL; stop infusion and call MD;
see instruction #5 below see instruction #5 below
Do not restart insulin infusion Do not restart insulin infusion
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until BG >100 mg/dLa until BG >100 mg/dLa

BG 80-120; decrease drip by 0.5 U/h BG 80-120; decrease drip by 0.2 U/h
BG 121-180; no change in drip rate BG 121-180; no change in drip rate
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BG 181-250; increase drip by 0.5 U/h BG 181-250; increase drip by 0.2 U/h
BG >250 bolus 5 U regular insulin IV and BG >250 bolus 2 U regular insulin IV and
increase drip by 0.5 U/h increase drip by 0.2 U/h
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5. For a BG <80 mg/dL or >400 mg/dL on insulin infusion, call MD

⊠ BG <80 mg/dL but >60 mg/dL, stop insulin infusion; check BG every 15 min
⊠ BG ≤60 mg/dL, stop insulin infusion; give 50-mL D50W IV push; check BG every 15 min and repeat treatment until BG ≥100 mg/dL. When BG
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≥100 mg/dL, call MD for new insulin infusion rate

⊠ BG >400 mg/dL, call MD to reassess insulin infusion rate
⊠ If TPN or tube feeds are interrupted for longer than 30 min, start D10W at 50 mL/h. Notify MD about change and future action
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6. When converting to subcutaneous (SQ) insulin, give prescribed SQ dose 30 min prior to discontinuing insulin infusion. Use Adult
SQ Insulin Order Sheet
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7. If patient eating meals give ______ U aspart SQ after patient eats carbohydrates and continue insulin infusion
8. Discontinue insulin infusion maintenance IV fluids when insulin infusion discontinued
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Check BG every hour with glucose meter until stable (range 100-180 mg/dL) for two consecutive readings and then every 2 hours.
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After surgery, when the patient has resumed an adequate oral Targets for Glucose Control in the
intake, intravenous administration of insulin and dextrose can be
stopped half an hour after the first subcutaneous insulin injection.
Hospitalized Patient
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Insulin needs may vary in the first several days after surgery A number of studies have observed that hospitalized patients with
because of continuing postoperative stresses and because of vari- diabetes and those with new-onset hyperglycemia (ie, those without
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able caloric intake. In this situation, multiple doses of regular a preadmission diagnosis of diabetes) have higher inpatient morbid-
insulin, guided by blood glucose determinations, can keep the ity and mortality. Also, poor glucose control in diabetics at admis-
patient in acceptable metabolic control. sion is associated with increased size of myocardial infarction and in
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In the intensive care units, glucose levels are controlled most some studies increased nosocomial infections after surgery. These
frequently using insulin infusions. Patients on total parental nutri- observations have led to the question of whether lowering glucose
tion (TPN) can have insulin added to the bag. Standard TPN levels close to normal in the hospital improves outcomes.
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contains 25% dextrose, so 50-mL/h infusion delivers 12.5 g of Initial studies of patients in surgical and medical ICUs sug-
dextrose per hour. gested that aggressive treatment of hyperglycemia (blood glucose
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On the general surgical and medical wards, most patients are <110 mg/dL) reduced mortality and morbidity. A large multi-
managed on subcutaneous insulin regimens. Limited cross-sectional center, multinational study (NICE-SUGAR), however, failed to
and prospective studies suggest that the best glucose control is confirm these reports. This study recruited 6104 surgical and
achieved on a combination of basal and bolus regimen with 50% of medical ICU patients with hyperglycemia (20% had diabetes) and
daily insulin needs provided by intermediate or long-acting insulins. randomized them to tight control (81-108 mg/dL) or less tight
Standardized order sets prompt medical personnel to write more control (<180 mg/dL). The tight group achieved blood glucose
physiological insulin orders, reduce errors, and include algorithms levels of 115 ± 18 and the conventional group 144 ± 23. There
for recognition and treatment of hypoglycemia (see http://ucsfinpa- were more deaths (829 vs 751) in the tight glucose control group
tientdiabetes.pbworks.com for examples). Table 17–24 is an compared to the less tight glucose control group (p = 0.02). The
example of one such order set for a subcutaneous insulin regimen. intensively treated group also had more cases of severe

TABLE 17–24 Example of a standardized subcutaneous insulin order set for inpatient use.
1. Check blood glucose and give insulin before meals, bedtime, and 2 am.
2. Discontinue previous SQ insulin order.
3. If patient becomes NPO for procedure/stops eating:
• HOLD nutritional dose of rapid-acting analog
• Give correctional dose of rapid-acting analog if BG >130 mg/dL
• Give glargine dose. If BG has been <70 mg/dL in last 24 h, call MD to consider adjusting glargine dose
• Call MD for NPO orders if patient on 70/30, NPH insulin or has been NPO >12 h
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A. Basal and nutritional insulin dose (in units):
Time Breakfast Lunch Dinner Bedtime

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Rapid-acting analog
NPH
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Insulin glargine
Insulin mixture
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B. Meal time correctional insulin with rapid-acting analog. Check box to choose scale. Add or subtract from nutritional dose of
rapid-acting analog.
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□ Sensitive □ Average BMI

BMI <25 and/or 25-30 and/or □ Resistant BMI
Blood Glucose Range <50 U/d 50-90 U/d >30 and/or >90 U/d □ Custom
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<70 mg/dL Treat for hypoglycemia per protocol (see order #6). Once BG •100 mg/dL give rapid-acting analog
Once BG • 100, give with following change when patient eats:
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2 U less 3 U less 3 U less - - - U less

70-100 1 U less 2 U less 3 U less - - - U less
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101-130 Give nutritional rapid-acting insulin as in #4A

131-150 +0 +1 +2 +---
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151-200 +1 +2 +3 +---
201-250 +2 +4 +6 +---
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251-300 +3 +6 +9 +---
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301-350 +4 +8 + 12 +---
351-400 +5 + 10 + 15 +---
>400 +6 + 12 + 18 +---
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C. ⊠ Bedtime and 2 am correctional insulin with rapid-acting analog if BG ≥200 mg/dL.
BG Range (mg/dL) Default Value (U) Custom
up
200-250 1 ---U
251-300 2 ---
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>300 3 ---
4. Call MD for BG <70 mg/dL or >400 mg/dL.
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5. For BG <70 mg/dL, use Hypoglycemia Protocol below. These hypoglycemia orders remain active for duration of SQ insulin
administration. For patient taking PO, give 20 g of oral fast-acting carbohydrate per patient preference:
⊠ Give 4 glucose tablets (5 g glucose/tablet). Repeat Q 15 min until BG ≥100 mg/dL.
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or
⊠ Give 6 oz fruit juice. Repeat Q 15 min until BG ≥100 mg/dL.
⊠ Give 25-mL D50W IV push if patient cannot take PO. Repeat Q 15 min until BG ≥100 mg/dL.
⊠ Check fingerstick glucose every 15 min and repeat treatment until BG is ≥100 mg/dL.
6. Discontinue above monitoring and intervention orders when SQ insulin is discontinued.
Note: Glargine (Lantus) cannot be mixed with any other insulin. Give glargine as a separate injection.

hypoglycemia (206 vs 15 cases), and the excess deaths in the inten- increased provision of substrate FFA. The increased FFAs contrib-
sive group were due to cardiovascular events. ute to the marked reduction in insulin-mediated glucose uptake
A study on tight intraoperative glycemic control during cardiac by skeletal muscle characteristic of late pregnancy. As a net result,
surgery also failed to show any benefit; if anything, the intensively during the third trimester, pregnant women without diabetes run
treated group had more events. The United Kingdom Glucose slightly higher blood glucose and ketone levels than nondiabetic
Insulin in Stroke Trial (GIST-UK) failed to show beneficial effect subjects, and women with preexisting diabetes that do not adjust
of tight glycemic control in stroke patients; however, the investiga- therapy appropriately can develop severe hyperglycemia.
tors acknowledged that, because of slow recruitment, the study The fetus also plays a role in the maintenance of the maternal
was underpowered. to fetal glucose gradient—the fetal glucose levels being deter-
Thus, based on the evidence available so far, ICU patients with mined by fetal insulin levels and the fetal insulin sensitivity.
diabetes and new-onset hyperglycemica with blood glucose levels Maternal hyperglycemia due to inadequate control of maternal
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above 180 mg/dL should be treated aiming for target glucose levels diabetes early in pregnancy will lead to an increase in fetal glucose
between 140 mg/dL (7.8 mmol/L) and 180 mg/dL (10 mmol/L). levels, fetal hyperinsulinemia, and large for gestational age fetus.
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Targeting blood glucose control in the intensive care unit close to

100 mg/dL (5.6 mmol/L) has not been proven to be beneficial Pregnancy in Women with Preexisting
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and may even be harmful. When patients leave the ICU, target
glucose values between 100 mg/dL and 180 mg/dL may be appro-
Diabetes
A. Prevalence The prevalence of pregestational diabetes in
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priate, although this view is based on clinical observations rather

than conclusive evidence. pregnant women is increasing. In the United Kingdom, the preva-
lence of type 1 diabetes increased from 1.56 to 4.09 per 1000
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pregnancies between 1995 and 2015. For type 2 diabetes, the

DIABETES MELLITUS AND PREGNANCY prevalence increased from 2.34 to 5.09 per 1000 pregnancies
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between 1995 and 2008 with a more rapid increase to 10.62 per
Hormone and Fuel Balance During 1000 pregnancies by 2012.
Pregnancy
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B. Maternal, fetal, and neonatal consequences of pres-

During pregnancy, the rapidly growing fetus impacts metabolism ence of diabetes during pregnancy If diabetes is poorly
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in the mother and causes profound hormonal and metabolic controlled in the first weeks of pregnancy, the risks of spontaneous
changes. These changes significantly affect the management of abortion and congenital malformation of the infant are increased.
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preexisting diabetes, and can precipitate hyperglycemia and diabe- Poor glycemic control later in pregnancy is associated with still
tes in previously nondiabetic mothers. births, fetal macrosomia, polyhydramnios, and neonatal hypogly-
Early in pregnancy, the hormones of pregnancy initiate
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cemia. Preexisting diabetes-related complications, particularly

changes that prepare the mother for the increasing nutrient gastroenteropathy, retinopathy, and nephropathy can impact both
requirements of the fetus late in pregnancy. Fat deposition is
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the pregnant woman and the fetus.

accentuated in early pregnancy due to enhanced conversion of
glucose to triglyceride after meals in pregnant compared with Congenital anomalies Poorly controlled diabetes in the first
nonpregnant subjects. Elevated prolactin and placental lactogen weeks of pregnancy raises the risks of spontaneous abortion and
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drive the production of serotonin by the β cell, which leads to β cell congenital anomalies of the infant. The commonest anomalies are
expansion, a process that peaks in mid gestation. β cell mass
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cardiac, neural tube defects, and genitourinary abnormalities.

approximately doubles during pregnancy, and both β cell glucose Their incidence compared to the normal population and their
sensitivity and insulin secretory capacity increase. At the same presumed time of occurrence during embryonic development are
time, α cell mass and glucagon secretion remain unchanged.
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listed in Table 17–25. The rate of anomalies is higher in diabetic

As the pregnancy progresses and nutrient utilization by the women with poor preconception control. Observational studies
fetus increases, plasma concentrations of glucose in the fasting demonstrate a linear relationship between glycated hemoglobin
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state tend to decline slightly. Since the flow of glucose and other levels and malformation rates. From a systematic review of several
nutrients to the fetus depends on the gradient across the placenta, observational studies, it was estimated that the relative risk reduc-
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maintenance of maternal glucose levels becomes increasingly tion of congenital anomalies for each 1% decrease in HbA1c
important and is achieved through increasing insulin resistance in ranged from 0.39 to 0.59. Attending preconception clinics with
the liver, muscle, and adipose tissue. Several pregnancy hormones intensive diabetic management instituted prior to conception and
contribute to insulin resistance, but progesterone, which increases continued through early pregnancy, results in significant reduc-
steadily through pregnancy and peaks shortly prior to parturition, tion in the frequency of anomalies—to rates near the population
provides the major drive. Glucose availability for the fetus norms.
increases as increased lipolysis in adipose tissue leads to a shift
toward fatty acid utilization by maternal tissues. Ketogenesis is Polyhdramnios Later in pregnancy, polyhydramnios, a com-
also accentuated in the postabsorptive state during pregnancy, mon complication in women with poorly controlled diabetes, may
secondary to hormonal effects on the maternal liver cells and lead to preterm delivery. Polyhydramnios also increases the risk for

TABLE 17–25 Congenital malformations in infants endogenous insulin secretion) in their cord sera or amniotic fluid
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of diabetic mothers. than in those with birth weights appropriate for gestational age.
Monkey fetuses with insulin-releasing pellets implanted in utero
Latest become macrosomic. Other metabolic substrates that cross the
Ratio of Gestational Age
Incidences for Occurrence
placenta, such as branched-chain amino acids may also play a role
Diabetic vs (Weeks after in fetal macrosomia, and transplacental lipids could contribute to
Control Group Menstruation) fat deposition.
Caudal regression syndrome 252 5 Prevention of maternal hyperglycemia throughout pregnancy
(due to premature termi- can reduce the incidence of macrosomia. The glycemic threshold
nation of the vertebral for fetal macrosomia seems to be postprandial peak values above
column—resulting in 130 mg/dL (7.2 mmol/L). On the other hand, excessively tight
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agenesis of the sacrum

and coccyx and/or malfor- glycemic control (average peak postprandial blood glucose levels
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mations of the pelvis and <110 mg/dL [6.1 mmol/L]) can be associated with insufficient
legs) fetal growth and small-for-date infants.
Anencephaly 3 6 Complications of macrosomia include fetopelvic disproportion
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Spina bifida, hydrocephalus, 2 6 leading to shoulder dystocia and its attendant risk for brachial
or other central nervous plexus injury and humeral and clavicle fractures. The neonate
system defects
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with macrosomia is also at increased risk for hypoglycemia, hyper-

Cardiac anomalies 4 bilirubinemia, hypocalcemia, respiratory distress syndrome, and
Transposition of great vessels 7 polycythemia.
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Ventricular septal defect 8 Adverse maternal outcomes of difficult vaginal delivery include
severe perineal lacerations and subsequent urinary and/or fecal
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Atrial septal defect 8

incontinence.
Anal/rectal atresia 3 8
Renal anomalies 5 Intrauterine growth retardation The fetus of a woman with
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Renal agenesis 6 7 diabetes of long duration and vascular disease may suffer intrauter-
Cystic kidney 4 7 ine fetal growth restriction related to inadequate uteroplacental
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perfusion. All body diameters may be below normal on ultrasono-

Ureter duplex 23 7
graphic measurements, but the abdominal circumference is espe-
Situs inversus 84 6
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cially affected, and oligohydramnios and abnormal Doppler flow

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Data from Kucera J. Rate and type of congenital anomalies among offspring of dia- measurements of the umbilical cord are common. In these patients
betic women. J Reprod Med. 1971;7:61; and Mills JL, Baker L, Goldman AS. Malforma-
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provision of adequate rest, meticulous control of hypertension (tar-

tions in infants of diabetic mothers occur before the seventh gestational week:
implications for treatment. Diabetes. 1979;28:292. get <135/85 mm Hg), maintenance of normal blood glucose levels,
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and intensive fetal surveillance are all essential for success.
placenta abruptio and postpartum uterine atony. Polyhydramnios Intrauterine death Prior to the 1970s, the incidence of appar-
ently sudden intrauterine fetal demise in the third trimester of
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is an excess volume of amniotic fluid (>1000 mL, often >3000 mL).

It is most often associated with fetal macrosomia. The excess vol- diabetic pregnancies was at least 5%. Except for congenital mal-
formations, the cause of stillbirth is often not obvious. The risk is
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ume of amniotic fluid is not related simply to the concentration

of glucose or other solutes in amniotic fluid or to excess fetal urine greater with poor diabetic control, and the incidence of fetal death
output as measured by change in bladder size on ultrasonography. exceeds 50%, if ketoacidosis develops in the mother. Some
instances of fetal demise are associated with preeclampsia-eclampsia,
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Other possible factors include decreased fetal swallowing, decidual

and amniotic fluid prolactin, and as yet unknown determinants of which is more common in pregnancies complicated by diabetes.
the complicated multicompartmental intrauterine transfer of Fetal death has also been associated with pyelonephritis—this is
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water. Polyhydramnios is rare in women with well-controlled now largely prevented by screening for and treating asymptomatic
diabetes. bacteriuria. Other than these known risk factors, one can presume
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(based on experimental studies) that the combination of fetal

Fetal macrosomia Many fetuses of poorly controlled diabetic hyperglycemia and hypoxia leads to acidosis and myocardial dys-
mothers are macrosomic (birth weight >90th percentile for gesta- function. Good glycemic control in diabetic women greatly
tional age), with increased fat stores, increased length, and reduces the risk of stillbirth.
increased abdomen-to-head or thorax-to-head ratios. The hypoth-
esis that fetal macrosomia results from the causal chain of mater- Neonatal hypoglycemia Hypoglycemia is common in the
nal hyperglycemia → fetal hyperglycemia → fetal hyperinsulinemia first 48 hours after delivery from previously hyperglycemic moth-
→ fetal macrosomia has been confirmed by clinical and experi- ers and is defined as blood glucose below 36 mg/dL (2.0 mmol/L)
mental studies. Macrosomic infants of diabetic mothers have sig- regardless of gestational age. The risk is as high for infants of
nificantly higher concentrations of C peptide (representing mothers with type 2 diabetes as type 1 diabetes. Neonatal

hypoglycemia is most closely linked to poor maternal glucose approximately 6% may have renal failure at follow-up several years
control and elevated fetal insulin levels during labor and delivery, after pregnancy. The latter figure may not be different from the
although data from amniotic fluid insulin studies suggest that the course of diabetic nephropathy in nonpregnant women with this
more hyperinsulinemic the fetus in the late third trimester, the level of renal dysfunction. If initial renal function in pregnancy is
higher the risk of neonatal hypoglycemia. Infants of diabetic impaired (serum creatinine >1.2 mg/dL [>106 μmol/L]; creatinine
mothers may also have deficient catecholamine and glucagon clearance <80 mL/min), then 35% to 40% are expected to show
secretion, and the hypoglycemia may be related to diminished further decline during pregnancy, and 45% to 50% have renal failure
hepatic glucose production and oxidation of free fatty acids. The at follow-up several years later. Thus, careful preconception counsel-
symptomatic infant may be lethargic with associated apnea, tachy- ing is important for these patients and their family members.
pnea, cyanosis, or seizures. Early feeding with 10% dextrose in
water by bottle or gavage by 1 hour of age should be instituted in
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the at-risk neonate. If this is not successful, treatment with intra- Management
venous dextrose solutions is indicated. There are usually no long- Pregnant women with preexisiting diabetes should ideally receive
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term sequelae of episodes of neonatal hypoglycemia. Keeping care in a multidisciplinary clinic staffed by obstetricians, endocri-
maternal blood glucose levels below 144 mg/dL and tight glyce- nologists, diabetes nurse specialists, dietitians, and specialist mid-
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mic control during labor can reduce the frequency of neonatal wives. There is substantial evidence that this improves the
hypoglycemia. outcomes in women with pregestational diabetes.
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Diabetic gastroenteropathy In early gestation, diabetic gas- Preconception counseling All diabetic women of reproduc-
troparesis can severely exacerbate the nausea and vomiting of tive age should be counseled to use adequate birth control and
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pregnancy (hyperemesis gravidarum), which sometimes continues plan their pregnancies. Before any planned pregnancy, the couple
into the third trimester. Drugs stimulating gastric motility such as should be referred for preconception assessment and counseling.
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erythromycin may be useful, but many patients with this compli- There should be assessment and discussion regarding management
cation require hyperalimentation to achieve nutritional intake of diabetic complications. Baseline measurements should include
adequate for fetal development. thyroid function tests including autoantibodies; early morning
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spot urine albumin/creatinine ratio; urinalysis to rule out asymp-

Diabetic retinopathy Background diabetic retinopathy may tomatic bacteruria; retinal examination; and cardiological assess-
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develop or progress during pregnancy, but it usually regresses post- ment in high-risk patients such as those with evidence of
partum. If background retinopathy is already present in early preg- microvascular disease. ACE inhibitors and ARBs cannot be used
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nancy, the rate of progression to neovascularization over the course during pregnancy. If necessary, alternative antihypertensive agents
of the pregnancy (proliferative diabetic retinopathy) is 6% if the that are safe for use in pregnancy (methyldopa, nifedipine, amlo-
dipine, labetolol) should be prescribed. Lipid-lowering therapies
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background retinopathy is mild; 18% if it is moderate; and 38% if

severe preproliferative changes are present. The risk factors for pro- are also contraindicated, and lipid abnormalities must be managed
by dietary measures. There should be discussion of risks and
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gression to proliferative retinopathy include poor glycemic control

before and during early pregnancy, rapid improvement in glycemic expected management strategies in the pregnancy. The patient
control during pregnancy, hypertension, and perhaps the many should be given glycemic goals with the aim of achieving control
as close to normal as possible before conception.
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growth factors derived from placental tissue. These risks are an

important reason to institute intensified preconception management
Glucose and insulin management Women are seen every 2
up
of diabetes. During pregnancy, sequential ophthalmologic examina-

tions are essential in women with type 1 or type 2 diabetes, and laser to 4 weeks in the first and second trimester and then every 1 to
photocoagulation treatment of the retina may be necessary. 2 weeks until 36 weeks and then weekly to term. The goal of
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glucose management during pregnancy is to prevent both pre-

Diabetic nephropathy The risk of worsening of diabetic prandial and postprandial hyperglycemia. Patients with type 2
nephropathy during pregnancy depends on baseline renal function diabetes on oral agents are usually switched to insulin treatment
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and the degree of hypertension. Total urinary albumin excretion during pregnancy. There are small nonrandomized studies sug-
does not increase substantially in normal pregnancy, but total uri- gesting that metformin use is safe in the first trimester. The drug
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nary protein collections, which obstetricians have used to define does cross the placenta, but it has not been associated with terato-
preeclampsia, may show a twofold increase in uncomplicated gesta- genesis. Glyburide was thought not to cross the placenta and has
tion. Diabetic women with microalbuminuria (30-299 mg/24 h) been considered safe for use in pregnancy. More recently it has
may have worsening of the albuminuria during pregnancy and been found that glyburide does cross the placenta and fetal gly-
15% to 45% develop the preeclamptic syndrome. Albuminuria buride levels are approximately 70% of maternal plasma levels.
usually regresses postpartum. Women with macroalbuminuria Until larger randomized control studies of metformin and gly-
(24-hour urinary albumin >300 mg) and well-preserved renal buride use at conception and early pregnancy are available, cau-
function (serum creatinine <1.2 mg/dL [<106 μmol/L]; creatinine tion should be exercised regarding their use early in pregnancy.
clearance >80 mL/min) at the beginning of pregnancy are likely to Perinatal outcome is optimal if patients aim for fasting
have moderate decline in renal function during gestation, and plasma glucose levels below 100 mg/dL (5.6 mmol/L) and

postprandial levels below 130 mg/dL (7.2 mmol/L). For patients TABLE 17–26 Schedule of obstetric tests and
with a history of recurrent severe hypoglycemic reactions, some- procedures.
what higher blood glucose targets should be selected. Self-monitoring
of capillary blood glucose should be performed eight or more Risk Based on Glycemic
Control, Presence of Vascular
times a day. Occasional monitoring in the middle of the night is Disease
recommended to monitor for nocturnal hypoglycemia. There is
evidence that CGM systems may be helpful in reducing both Procedure Low Risk High Risk
hyperglycemia and hypoglycemic excursions. These systems do Ultrasound to date gestation 8-12 wk 8-12 wk
not replace self-monitoring of blood glucose but allow for fine- Prenatal genetic diagnosis As needed As needed
tuning of glycemic control and alert the patient to rapid changes
Targeted perinatal ultrasound; 18-22 wk 18-22 wk
in glucose levels. One randomized study showed that pregnan-
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fetal echocardiography
cies using CGM had better glycemic control in the third trimes-
Fetal kick counts 28 wk 28 wk
ter and lower risk of macrosomia. Clinical trials using continuous
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a
glucose monitors during pregnancy are currently underway. Ultrasound for fetal growth 28 and 37 wk Every 3-8 wk
Confirmation of long-term control is provided by sequential Antepartum FHR monitoring, 36 wk, weekly 27 wk,
backup with biophysical profile 1-3 per wk
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measurement of glycosylated hemoglobin and fructosamine

every 4 to 6 weeks. Amniocentesis for lung … 35-38 wk
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b
Patients should see the nutritionist to assess caloric needs and Induction of labor 41 wk 35-38 wk
get instructed on carbohydrate counting. The caloric intake is a
Not needed in normoglycemic, diet-treated women with gestational diabetes mellitus.
based on ideal body weight and it is approximately 30 to 35 kcal/kg b
Earlier for obstetric reasons or for impending fetal macrosomia.
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for normal-weight women; about 24 kcal/kg current weight for

overweight women; and 10 to 15 kcal/kg current weight for obese
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women. All patients should learn how to self-adjust their doses of continuous glucose monitors is encouraged. Hypoglycemic reac-
short-acting insulin based on planned carbohydrate load or pre- tions have not been associated with fetal death or congenital
meal blood glucose levels. anomalies, but they pose a risk to maternal health.
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Type 1 patients are typically on a basal-bolus insulin regimen

Fetal monitoring (Table 17–26) First-trimester ultrasound is
(see Table 17–15). Regular insulin, insulin aspart, and insulin
often obtained to document viability, as the rate of miscarriage is
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lispro are the approved bolus insulins; and NPH and insulin
higher in women with diabetes, and to estimate gestational age. A
detemir are used for basal coverage. Studies on insulin glargine use
second-trimester, detailed ultrasound examination of fetal anat-
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during pregnancy are limited. Retrospective case control studies

omy is performed at approximately 18 weeks for detection of
have not shown any adverse effects of glargine use at the time of
congenital anomalies. Ultrasound examination in the third trimes-
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conception and during pregnancy. Many type 1 patients elect to

ter (at 28-32 weeks and 38 weeks) is performed to assess fetal
use insulin pumps during pregnancy. Since the risk of diabetic
growth.
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ketoacidosis is increased with pump use, it is especially critical that

patients have adequate instruction on the use of insulin pumps Antepartum fetal testing is recommended using fetal move-
and can troubleshoot any problems that may arise. ment counting, biophysical profile, nonstress test (NST), and/or
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Women with type 2 diabetes can be managed with regular contraction stress test (CST) initiated at 32 to 34 weeks of gesta-
insulin or short-acting insulin analogs before meals and NPH or tion. Most simply, the infrequency of fetal movement as noted in
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insulin detemir at bedtime. Sometimes NPH or insulin detemir is regular fetal kick counts (fewer than four per hour) may indicate
also required in the morning. fetal jeopardy. The fetal biophysical profile is a rigorous analysis of
Total insulin requirements vary during gestation. There is usu- fetal activity patterns using ultrasound to assess gross body move-
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ally an increase in insulin dose between weeks 3 and 7, then a ments, the tone of the limbs, and chest wall motions as well as
slight decrease between weeks 7 and 15 followed by a gradual reactivity of the fetal heart rate (FHR) and the volume of amniotic
increase until about week 35. The insulin requirements in type 1 fluid. The presence of FHR accelerations and long-range variabil-
at
diabetes at around 35 weeks (1.0 U/kg/24 h) are almost double ity on the NST and the absence of late decelerations (lower FHR
the prepregnancy requirements. Women with type 2 diabetes usu- persisting after the contraction subsides) on the CST indicate that
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ally start out with higher doses and may eventually require as the fetus is well oxygenated. Generally, the NST and CST are
much as 1.5 to 2 U/kg/24 h. Exercise can improve insulin sensitiv- sensitive screening tests, and abnormal results of FHR monitoring
ity and should be encouraged in type 2 patients. The benefits of in these tests overestimate the diagnosis of fetal distress. Therefore,
exercise are less obvious in women with type 1 diabetes, and there it is wise to obtain additional evidence of fetal jeopardy (by bio-
is always a concern about exercise-induced hypoglycemia. physical ultrasonographic assessment) before cesarean delivery is
Hypoglycemic reactions are more frequent and sometimes recommended in preterm pregnancies. In term gestation with
more severe in early gestation but are a risk at any time during abnormal fetal testing, there is little to be gained by continuing
pregnancy. Therefore, insulin-treated patients should take snacks the pregnancy. In complicated patients with IUGR, olighohy-
between meals and at bedtime to prevent hypoglycemia. Family dramnios, preeclampsia, or poor blood glucose control, testing
members should be instructed in the use of glucagon. The use of may start as early as 26 weeks and is performed more frequently.

Timing of delivery Unless maternal or fetal complications TABLE 17–27 Protocol afor intrapartum insulin
arise, the goal for delivery in diabetic women should be 38 to infusion.
41 weeks in order to reduce neonatal morbidity from preterm
Intravenous Fluids
deliveries. On the other hand, the obstetrician may wish to induce If blood glucose is >130 mg/dL (>7.2 mmol/L), infuse mainline Ringer
labor before 39 weeks, if there is concern about increasing fetal lactate at a rate of 125 mL/h.
weight. Before a preterm delivery decision (<37 weeks) is made or If blood glucose is <130 mg/dL (<7.2 mmol/L), infuse mainline Ringer
delivery is considered in women with poor glycemic control at 37 to lactate to keep vein open and begin Ringer lactate and 5%
dextrose at a rate of 125 mL/h controlled by infusion pump.
38 weeks of gestation, fetal pulmonary maturity should be deter-
Insulin Infusion
mined. Tests for maturity using amniocentesis assess risk of neo- Mix 100 U of regular human insulin (U100) in 100 mL NaCl 0.9% and
natal respiratory distress syndrome and include the piggyback to mainline. The concentration is 1 U/mL. Adjust intrave-
lecithin-sphingomyelin (L/S) ratio, phosphatidylglycerol, and
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nous insulin hourly according to the following table when the

other biochemical or physical assays of surfactant activity. In preg- blood glucose is >70 mg/dL (>3.9 mmol/L). Target blood glucose
70-110 mg/dL.
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nancies complicated by hyperglycemia, fetal hyperinsulinemia can

lead to low pulmonary surfactant apoprotein production. The Blood Glucose
lowest risk of respiratory distress syndrome is attained by delaying in mg/dL Gestational
(mmol/L) Type 1 Type 2 Diabetes Custom
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delivery (if possible) until 38 to 41 weeks and minimizing the

need for cesarean sections. <70 (<3.9) No No No
insulin insulin insulin
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Route of delivery Once fetal lung maturity is likely, the route 71-90 (3.9-5) 0.5 U/h No No
insulin insulin
of delivery must be selected based on the usual obstetric indica-
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tions. If the fetus seems large (>4200 g) on clinical and ultrasono- 91-110 (5.1-6.1) 1 1 U/h No
insulin
graphic examination of diabetic women, cesarean section probably
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should be performed because of the possibility of shoulder dysto- 111-130 (6.2-7.2) 1.5 2 1 U/h
cia and birth trauma. Otherwise, induction of labor is reasonable, 131-150 (7.3-8.3) 2 3 2
because maternal and peripartum risks are fewer following vaginal 151-170 (8.4-9.4) 2.5 4 3
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delivery. Once labor is underway, continuous FHR monitoring is 171-190 3 5 4

essential. Maternal blood glucose levels greater than 150 mg/dL (9.5-10.6)
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(8.3 mmol/L) can be associated with intrapartum fetal hypoxia. >190 (>10.6) Call MD and check urine ketones
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a
Protocol useful also for diabetic pregnant women who are “NPO” or being treated
Insulin and glucose management during labor and with beta-adrenergic tocolysis or corticosteroids. The scale dosages may need to be
delivery It is important to avoid maternal hyperglycemia dur- doubled for the latter. Boluses of short-acting insulin must be used to cover meals.
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ing labor because it increases the risk for fetal acidemia and neo-
natal hypoglycemia. The goal is to maintain glucose levels between plan initial therapy for the sick infant if required. Infants of moth-
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70 and 110 mg/dL (3.9-6.1 mmol/L). Maternal glucose levels ers with poorly controlled diabetes have an increased risk of respi-
above 180 mg/dL (10 mmol/L) are consistently associated with ratory distress syndrome. Possible reasons include abnormal
neonatal hypoglycemia. During the latent phase of labor, maternal production of pulmonary surfactant or connective tissue changes
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metabolic demands are fairly stable but there is significant energy leading to decreased pulmonary compliance. However, in recent
expenditure during active labor and delivery and insulin needs are years, the incidence of respiratory distress syndrome in these preg-
up
minimal. Glucose control is typically managed using intravenous nancies has declined from 24% to 5%, probably related to better
dextrose (at 100-125 mL/h) and insulin infusions (Table 17–27). maternal glycemic control, selected use of amniotic fluid tests, and
After delivery of the placenta, the insulin-resistant state rapidly delivery of most infants at term. Other possible problems in
lic
disappears, and insulin requirements are close to prepregnancy infants of diabetic mothers include hypocalcemia less than 7 mg/dL
levels. Type 1 or type 2 patients who were previously on insulin (1.75 mmol/L), hyperbilirubinemia greater than 15 mg/dL
can go back to their usual prepregnancy insulin regimens and
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(256 μmol/L), polycythemia (central hematocrit >70%), and poor

doses once they start eating. Type 2 patients who were on oral feeding. These complications are presumably related to fetal
agents prepregnancy frequently do not require any medication hyperglycemia and hyperinsulinemia and probably to intermittent
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during the first 24 to 48 hours postpartum. They can stay on low-level fetal hypoxia. Improved control of the maternal diabetic
insulin while breastfeeding or go on metformin or glyburide state has reduced their incidence.
which are safe while breastfeeding.
Neonatal management Planning for the care of the infant Gestational Diabetes
should be started prior to delivery, with participation by the pedia- Gestational diabetes (GDM) is defined as glucose intolerance
trician or neonatologist in decisions about timing and manage- that develops or is first recognized during pregnancy. As insulin
ment of delivery. In complicated cases, the pediatrician must be in resistance increases during pregnancy, euglycemia depends on a
attendance to learn about antenatal problems, to assess the need compensatory increase in insulin secretion. Failure to compen-
for resuscitation, to identify major congenital anomalies, and to sate with increased insulin secretion leads to gestational diabetes.

As the increase in insulin resistance is greatest in the third tri- TABLE 17–28 Risk factors for gestational diabetes
mester, GDM usually develops going into this period. The mellitus.
prevalence of GDM in a population is reflective of the preva-
Maternal age >37 y
lence of type 2 diabetes in that population. In low-risk popula-
Ethnicity
tions, such as those found in Sweden, the prevalence in Indian subcontinent—11-fold
population-based studies is lower than 2% even when universal Southeast Asian—eightfold
testing is offered, while studies in high-risk populations, such as Arab/Mediterranean—sixfold
Afro-Caribbean—threefold
the Native American Cree, Northern Californian Hispanics, and Prepregnancy weight >80 kg or BMI >28 kg/m2
Northern Californian Asians, reported prevalence rates ranging Family history of diabetes in first-degree relative
from 4.9% to 12.8%. Other risk factors include a history of Previous macrosomia/polyhydramnios
macrosomia (birth weight >4000 g), polycystic ovarian syn- Previous unexplained stillbirth
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Polycystic ovarian syndrome

drome, essential hypertension or pregnancy-related hyperten-
sion, history of spontaneous abortions and unexplained still
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births, family history of diabetes, obesity, age older than 25 years,

and history of gestational diabetes (Table 17–28). other countries. The risk assessment for GDM (see Table 17–28)
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Women with GDM are at increased risk for urinary tract infec- should be performed at the first prenatal visit. Those women at
tions, pyelonephritis, asymptomatic bacteriuria, and preeclampsia. high risk should undergo OGTT testing as soon as feasible. If the
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There is a 10% risk of polyhydramnios. Fetal risks of poor glucose test is negative, then they should be retested at 24 to 28 weeks of
control include stillbirths and macrosomia. There is no increase in gestation. A fasting plasma glucose of more than or equal to 126
risk for congenital anomalies since the glucose intolerance devel- mg/dL or random glucose of more than or equal to 200 mg/dL
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ops later in pregnancy. confirmed on repeat testing is diagnostic of diabetes and negates
Strategies for diagnosis are outlined in Table 17–29. Currently, the need to perform a glucose challenge test. Lower risk women
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international consensus is lacking regarding the diagnostic criteria are screened for GDM using a two-step protocol performed at 24
for GDM. The 100 g 3-hour OGTT test is commonly used in the to 28 weeks. First, a glucose challenge test is performed using a 50 g
United States and the 75 g 2-hour WHO test is used in many glucose load. The patient does not have to be fasting. A 1-hour
y
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TABLE 17–29 Screening and diagnosis of gestational diabetes.

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Perform blood glucose testing at 24-28 wk

Two-step protocol:
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A. Glucose challenge test: 1-h plasma glucose after 50 g glucose load. Patient is not fasting.
≥140 mg/dL (≥7.8 mmol/L) identifies ~80% of women with GDM; ≥130 mg/dL (≥7.2 mmol/L)
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increases sensitivity to ~90%.

B. 100 g OGTT: If a woman meets or exceeds threshold on glucose challenge test then perform
fasting diagnostic 100 g OGTT within a week. The test is performed after an at least 8-h over-
night fast and after at least 3 d of unrestricted diet (≥150 g carbohydrate per day). Subject
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should be seated and should not smoke during test.

The test is positive if two of the following glucose levels are found.
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Carpenter/Coustan criteria National Diabetes Data group criteria

Fasting: ≥95 mg/dL (≥5.3 mmol/L) >105 mg/dL (5.8 mmol/L)
1 h: ≥180 mg/dL (≥10 mmol/L) >190 mg/dL (10.6 mmol/L)
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2 h: ≥155 mg/dL (≥8.6 mmol/L) >165 mg/dL (9.2 mmol/L)

3 h: ≥140 mg/dL (≥7.8 mmol/L) >145 mg/dl (8.0 mmol/L)
If one value is abnormal, repeat test in 4 wk
at
One step protocol proposed by International Association of the Diabetes and Pregnancy Study
Groups:
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Fasting glucose at first prenatal visit. Value >92 mg/dL (5.1 mmol/L) is diagnostic of GDM and no
additional testing is indicated. If negative then perform diagnostic 75 g OGTT testing at 24 to 28 wk
after overnight fast of 8 h. The test is positive if one of the following glucose levels is found.
Fasting: >92 mg/dL (5.1 mmol/L)
1 h: >180 mg/dL (10.0 mmol/L)
2 h: >153 mg/dL (8.5 mmol/L)
WHO Diagnostic criteria and classification of hyperglycemia first detected in pregnancy 2013.
IADPSG Consensus Panel Diabetes Care. 2010;33:676.
National Diabetes Data Group Diabetes. 1979;28:1039.
Carpenter MW, Coustan DR. Am J obstet Gynecol. 1982;144:768.

plasma glucose value of 140 mg/dL (7.8 mmol/L) or greater iden- underweight women (BMI <18.5 kg/m2) at the onset of preg-
tifies approximately 80% of women with GDM; decreasing the nancy. However, there are no data on optimal weight gain for
cutoff value to 130 mg/dL (7.2 mmol/L) increases the sensitivity women with GDM.
to approximately 90%. Women with the positive glucose chal- If fasting capillary blood glucose levels exceed 90 to 100 mg/dL
lenge test should undergo a 3-hour 100 g oral glucose tolerance (5-5.6 mmol/L) or if 1-hour or 2-hour postprandial glucose values
test within the week. are consistently greater, respectively, than 130 or 105 mg/dL (7.2 or
Although there is continuing debate regarding universal 5.8 mmol/L) therapy is begun with insulin. The total insulin dose
screening, recent studies are supportive of this position. An obser- varies from 0.7 to 2 U/kg. NPH or insulin detemir are the preferred
vational study of Caucasian women, where all were tested with the long-acting insulins. Insulin glargine has not been well studied.
oral glucose tolerance test, found that the prevalence of GDM Insulin aspart or lispro and regular insulin can be used. Hypoglyce-
among women with no risk factors was 2.8%. Excluding this low- mia is a risk factor with aggressive management of glucose levels
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risk group would still require 80% of women to be tested and with insulin. Patients and family members should be instructed on
would miss 10% of all cases of GDM. The Hyperglycemia and monitoring for and treating hypoglycemia.
ev
Pregnancy Outcome (HAPO) study reported a continuous rela- Metformin and glyburide have been considered as alternative
tionship between glucose concentration with the 28-week oral options to insulin therapy. Metformin does cross the placenta but
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glucose tolerance test and neonatal adiposity, cesarean sections, has not been associated with teratogenesis. The advantage of this
neonatal hypoglycemia, premature delivery, shoulder dystocia, drug is that it does not result in hypoglycemia. An open label study
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need for intensive neonatal care, hyperbilirubinemia, and pre- (the MiG trial) of 751 women with GDM at 20 to 33 weeks of
eclampsia. A study by Landon and colleagues of women with mild gestation randomized to either metformin or insulin did not show
GDM on a 100 g 3-hour glucose tolerance test found that treat- a difference in primary composite outcome of neonatal complica-
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ment reduced the risk of fetal overgrowth, shoulder dystocia, tions. Forty-six percent of the subjects on metformin did, however,
cesarean delivery, and hypertensive disorders. The United States require supplemental insulin. Langer and colleagues randomized
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Preventive Services Task Force on Preventive Health Care has 404 women with GDM at 11 to 33 weeks of gestation to glyburide
concluded that there is good evidence to support universal screen- therapy or insulin treatment. There was no significant difference in
ing for GDM after 24 weeks but not for universal screening earlier fetal outcomes in the two groups—large for gestational infants,
y
in pregnancy. Women who have a history of GDM with previous macrosomia, neonatal ICU admission, or fetal abnormalities. Target
pregnancy should undergo preconception counseling similar to glycemic control was achieved in 88% of patients on insulin and
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those patients with pregestational diabetes. They should begin to 82% on glyburide. There was significant reduction in maternal
monitor their glucose levels when they begin to try to conceive or hypoglycemic episodes in the glyburide group compared to the
o
as soon as their new pregnancy is confirmed. These women do not insulin group (2% vs 20%). A large retrospective observational
need retesting for GDM. study, however, has raised concerns about glyburide’s safety in gesta-
N
HbA1c values are helpful for assessment of pregestational diabe- tional diabetes. The study reviewed the fetal outcomes of approxi-
tes but are not helpful for management of GDM where they are mately 9000 women with gestational diabetes treated with either
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normal. glyburide or insulin. They found that infants of women treated with
The goal of therapy is prevention of fasting and postprandial glyburide had higher risk of respiratory distress, neonatal hypogly-
hyperglycemia. The Australian Carbohydrate Intolerance Study in cemia, birth injury, and large for gestational age.
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Pregnant Women (ACHOIS) trial found that intervention to Patients are usually scheduled for follow-up visits every 1 to
lower glucose levels to less than 100 mg/dL before meals and less 2 weeks. A 24-hour urine collection may be performed to establish
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than 126 mg/dL 2 hours after meals reduced the rate of serious baseline level of proteinuria and creatinine clearance due to the
perinatal outcomes (defined as death, shoulder dystocia, bone higher likelihood of preeclampsia. It is not necessary to routinely
fracture, and nerve palsy) from 4% to 1%. After diagnosis, the perform ophthalmic examinations in these patients unless there is
lic
patient should be placed on a diabetic meal plan modified for a strong suspicion of preexisting type 2 diabetes mellitus. Fetal
pregnancy. The caloric intake is based on ideal body weight—25 monitoring is warranted in those patients who are not well con-
to 35 kcal/kg ideal weight, 40% to 55% carbohydrate, 20% pro- trolled, requiring insulin therapy, or who have other complica-
at
tein, and 25% to 40% fat. Calories are distributed over three tions of pregnancy. The most commonly used test is a twice-weekly
meals and three snacks (see Table 17–24). Most patients can be nonstress test.
e
taught to count their carbohydrates and to read food labels. This If blood glucose levels are close to normal and there are no
caloric distribution will help 75% to 80% of patients to become other complications, the delivery can go to term. It is generally
normoglycemic. Patients should also be encouraged to participate recommended that the pregnancy does not go beyond term. Most
in moderate aerobic exercise such as walking or antenatal exercise patients do not require insulin during delivery. Blood glucose
classes, of at least 15- to 30-minutes duration, three or more times levels should be monitored the following day to ensure that the
a week. In normal pregnancy, expected weight gain varies accord- patient has reverted to normoglycemia. About 95% of patients
ing to the prepregnancy weight. The Fifth International Work- return to normal glucose status.
shop-Conference on GDM recommends a relatively small gain Progression to type 2 diabetes later in life occurs in 5% to 50%
during pregnancy of 7 kg (15 lb) for obese women (BMI ≥30 kg/m2) of women with gestational diabetes. The wide range in incidence
and a proportionally greater weight gain (up to 18 kg or 40 lb) for is influenced by body weight, family history, glucose levels, and

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17

Pancreatic Hormones and

Umesh Masharani, MB, BS, MRCP (UK) and

ABCC8 ATP-binding cassette transporter sub- ER Endoplasmic reticulum

family C member 8 FDA Food and Drug Administration

ADA American Diabetes Association FHR Fetal heart rate

AGPAT 1-acylglycerol-3-phosphate-O- GABA Gamma-aminobutyric acid

AKT/PKB AKR mouse tumor 8 kinase/protein

AIRE Autoimmune regulator GH Growth hormone

AMPK Adenosine monophosphate-activated GHSR Growth hormone-secretagogue receptor

APS1 Autoimmune polyendocrinopathy GIP Gastric inhibitory polypeptide

BMI Body mass index GLP-1 Glucagon-like peptide-1

CCK Cholecystokinin GLUT Glucose transporter

Cyclic 3′,5′-guanosine monophosphate

CST Contraction stress test HLA Human leukocyte antigen

17-Gardner_ch17-p595-682.indd 595 09/06/17 4:18 PM

IL-6 Interleukin-6 PERK Protein kinase R-like endoplasmic

ISL1 Islet transcription factor 1 Pancreatic transcription factor 1α

KPD Ketosis-prone diabetes RFX6 Regulatory factor X-6

Kir6.2 Potassium channel, inwardly-rectifying 6.2 transporter), member 2

adulthood SREBP1c Sterol regulatory element-binding

LDL Low-density lipoprotein

MODY Maturity-onset diabetes of the young TCF7L2 Transcription factor 7-like 2

NeuroD1 Neural differentiation factor 1 TNF-` Tumor necrosis factor-α

NIH National Institutes of Health UGDP University Group Diabetes Program

VLDL Very low density lipoprotein

PCSK Proprotein convertase, subtilisin/kexin

PDX1 Pancreatic duodenal homeobox-1 ZnT8 Zinc transporter 8

Zinc finger protein 57

THE ENDOCRINE PANCREAS ANATOMY AND HISTOLOGY

17-Gardner_ch17-p595-682.indd 596 09/06/17 4:18 PM

nucleus activates the transcription of the preproinsulin mRNA

granules contain insulin and C peptide in equimolar amounts and

sists of partially cleaved intermediates.

acids, which includes the A and B chains of the insulin molecule

prohormone-converting enzymes type 1 and 2 (PCSK1 and

acids, thereby removing the intervening sequence. After the two

pairs of basic amino acids are removed by carboxypeptidase E, the

A small amount of proinsulin produced by the pancreas

standard immunoassay for insulin cross-react with proinsulin;

human pancreas is actually proinsulin. Because proinsulin is not

17-Gardner_ch17-p595-682.indd 597 09/06/17 4:18 PM

Secretory granules (condensation and

Golgi (packaging of proinsulin into coated

Ca2+ Small transfer vesicles (transport of proinsulin

Nucleus (production of mRNA for preproinsulin

Granular endoplasmic reticulum (synthesis of

LEU SER GLY ALA GLY PRO

CYS A chain GLU

17-Gardner_ch17-p595-682.indd 598 09/06/17 4:18 PM

metabolism of glucose block the release of insulin. Glucose enters

proteins termed glucose transporters (GLUTs) (discussed later).

Period of glucose infusion

17-Gardner_ch17-p595-682.indd 599 09/06/17 4:18 PM

Glucose Catecholamines GLP-1

DAG and Voltage-gated

17-Gardner_ch17-p595-682.indd 600 09/06/17 4:18 PM

Inhibitors of Insulin Neural: α-adrenergic effect of

Drugs: diazoxide, thiazides, β-blockers,