Diabetes Mellitus

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The endocrine pancreas
Islets of Langerhans, contain four major cell types.

β cell secretes insulin decrease blood sugar

α cell secretes glucagon increase blood sugar
δ cells contain somatostatin
PP unique pancreatic polypeptide.
(pancreatic polypeptide)

Enterochromaffin VIP, that exerts several gastrointestinal effects, such as

stimulation of secretion of gastric and intestinal enzymes.

Diabetes Mellitus (DM)

 Diabetes mellitus is not a single disease entity but rather a group of
metabolic disorders sharing the common underlying feature of
hyperglycemia.

 Hyperglycemia in diabetes results from defects in insulin secretion

(cell resistance/ insulin deficiency), insulin action (insulin-resistant),
or most commonly, both.

 Diabetes is the leading cause of end-stage renal disease, adult-

onset blindness, and nontraumatic lower extremity amputations

 Prediabetes, defined as elevated blood sugar that does not reach

the criterion accepted for an outright diagnosis of diabetes ; persons
with prediabetes have an elevated risk for development of frank1
diabetes.

 Blood glucose level should be tightly regulated by insulin and

glucagon.
 insulin is an anabolic hormone; main effect on: skeletal muscles,
adipose tissue, liver (gluconeogenesis) no action on brain.
 GH, Glucagon are catabolic hormones.
1: Is the precursor stage before DM in which not all of the symptoms required to diagnose diabetes are
present, but blood sugar is abnormally high
 Diagnosis of DM:
 Normal blood glucose levels 70 to 120 mg/dL.

The diagnosis of diabetes is established by elevation of blood glucose by

any one of three criteria:

Test Blood Glucose level indicate DM

Random (at > 200 mg/dL, with classical signs and symptoms (like
anytime) blood increasing weight, Polydipsia , polyuria).
glucose
concentration
fasting glucose ≥126 mg/dL on more than one occasion(It is done on more
concentration than one occasion to avoid false dx).
(Minimum 8hrs)
oral glucose >200 mg/dL after 2hrs. From administering a standard
tolerance test carbohydrate load (75 g of glucose)
(OGTT)2 repeat to assure diagnosis

Those who have Pre-diabetes (Impaired glucose tolerance will show

the following results) :

Fasting Glucose 110-125 mg/dL

OGTT 140-199 mg/dL

 people with impaired glucose tolerance (prediabetes) have a significant risk for
progression to overt (Visible) diabetes over time.

 Boarder line or grey zone; higher tendency to develop diabetes

2: A glucose tolerance test measures how well your body’s cells are able to absorb glucose, or sugar, after you
ingest a given amount of sugar.
Classification of DM: you have to know the genes of MODY
 Type 1
diabetes Type 2 diabetes

starts with peripheral resistance despite

normal insulin level → progressive loss of
beta-cells function

is caused by a combination of
is characterized by an
absolute deficiency of
peripheral resistance to
insulin secretion caused by insulin action and an
pancreatic beta cell inadequate compensatory
destruction, usually response of insulin secretion
resulting from an by the pancreatic beta cells
autoimmune attack. (relative insulin deficiency).
Accounts for approximately
10% of all cases.
Accounts for approximately
80% to 90% of all cases..

Pathogenesis:
Pathogenesis:
-Type 2 diabetes is a
-Type 1 diabetes is an autoimmune prototypical complex
disease in which islet destruction is multifactorial disease .
caused primarily by immune
effector cells reacting against -Environmental factors such as
endogenous beta cell antigens. sedentary life style and dietary
habits .
-The classic manifestations of the
disease occur late in its course, -Genetic factors are also
after more than 90% of the beta involved in the pathogenesis
cells have been destroyed. -Recent Large-scale genome-
-The fundamental immune wide association studies , have
abnormality in type 1 diabetes is a identified more than a dozen
failure of self-tolerance in T cells. susceptibility loci called
“diabetogenic “ genes The
-Autoantibodies against a variety of
beta cell antigens, are detected in two defects that
the blood of 70% to 80% of characterize type 2 diabetes
patients. are :
-90% and 95% of white patients 1-Decreased ability of peripheral
with type 1 diabetes have HLA-DR3, tissues to respond to insulin
or DR4. (INSULIN RESISTANCE )
-Environmental factors, especially 2-Beta cells dysfunction that is
infections, may be involved too. manifested as inadequate
insulin secretion in the face of
insulin resistance and
hyperglycemia .
Obesity and insulin resistance:

 Insulin resistance is defined as the failure of target tissue to respond

normally to insulin . It leads to decreased uptake of glucose in
muscles .

Picture1 : multifactorial components leads to insulin resistance , then B-cells tries to

compensate by rising the production of insulin (hyperplasia) until it returns the glucose
blood level to normal . After a while , B-cells are tired of producing so much insulin , so
they start to secrete less insulin and here we will have (Impaired glucose tolerance) .
When the B-cells stops completely from secreting insulin (Failure) we will get diabetes .
Monogenic Forms of Diabetes

• Resembles type 2 DM, but occurs in young age group.

 Type 1 and type 2 diabetes are genetically complex ,no single-
gene defect (mutation) can account for predisposition to these
entities.
 By contrast, monogenic forms of diabetes are uncommon
examples of the diabetic phenotype occurring as a result of
loss-of-function mutations within a single gene.
 The largest subgroup of patients in this category traditionally
was designated as having maturity-onset diabetes of the
young (MODY) because of its superficial resemblance to type
2 diabetes and its occurrence in younger patients.
 MODY can be the result of inactivating mutations in one of six
genes.

MODY is caused by genetics defects in Beta cell function, due to mutations

:in
Hepatocyte Nuclear Factor 4α gene HNF4A MODY-1

Glucokinase gene GCK MODY-2

Hepatocyte Nuclear Factor 1α gene HNF1A MODY-3

Pancreatic and duodenal hemobox 1 gene PDX1 MODY-4

Hepatocyte Nuclear Factor 1β gene HNF1B MODY-5

Neurogenic differentiation factor 1 gene NEUROD1 MODY-6

Morphology

 Lesions in the pancreas are inconstant (not significant)and rarely of

diagnostic value. we don’t take pancreas biopsy for diagnosing diabetes,
Diagnosis is by biochemical tests.

One or more of the following alterations may be present:

In Type1 DM:
• Reduction in the number and size of islets. This change most often
is seen in Type1 DM.

• Insulitis: Leukocytic infiltration of the islets, which are principally

composed of mononuclear cells (lymphocytes and macrophages). It is
typically more in Type1 DM.

In Type2 DM:
• Amyloid replacement of islets in long-standing type 2
diabetes, appearing as deposition of pink, amorphous material. At
advanced stages fibrosis also may be observed.

Insulitis Amyloidosis
Type1 DM Type2 DM
Clinical Manifistations:

 Polyuria:when glucose
levels are so high that
glucose is excreted in the
urine. Water follows the
glucose concentration
passively, leading to
abnormally high urine
output.
 Polyghagia: glucose from
the blood cannot enter the
cells - due to either a lack
of insulin or insulin
resistance - so the body
can't convert the food you
eat into energy. This lack
of energy causes an
increase in hunger.
 Weight loss: insufficient
insulin prevents the body
from getting glucose from
the blood into the body's
cells to use as energy.
When this occurs, the body
starts burning fat and
muscle for energy, causing
a reduction in overall
body weight.
 Clinical manifistations
DM type 1 :
the classic triad of diabetes:
 Polyuria
 Polydipsia
 Polyphagia

 Despite the increased appetite, catabolic effects prevail, resulting in

weight loss and muscle weakness.
 In patients with type 1 diabetes, deviations from normal dietary
intake, unusual physical activity, infection, or any other forms of stress
may rapidly influence the metabolic balance, predisposing the affected
person to diabetic ketoacidosis3.
 The plasma glucose usually is in the range of 500 to 700 mg/dL
 The marked hyperglycemia causes an osmotic diuresis and dehydration
characteristic of the ketoacidotic state.

Type 2 DM:

May manifest with

 polyuria
 polydipsia Why in type 1 diabetes
patients may develop DKA
, while in type 2 they don’t
 But unlike in type 1 diabetes, patients often are ?
older than 40 years and frequently are obese. Because in Type 1 DM we
 In the decompensated state, patients with type dont have any insulin , so
the cells are not receiving
2 diabetes may develop hyperosmolar any glucose . Our body
nonketotic coma. This syndrome is engendered then has to convert fat
by severe dehydration resulting from sustained into ketone bodies to
osmotic diuresis and urinary fluid loss due to supply the cells with inurjy
, and the left amount of
chronic hyperglycemia. ketone bodies will be
 Typically, the affected person is an elderly accumulated in blood and
diabetic who is disabled by a stroke or an cause it to be acidic .
infection and is unable to maintain adequate Unlike type 2 diabetes
where you have
water intake. ”RELATIVE” amount of
insulin .

3:Without enough insulin, your body begins to break down fat as fuel. This
process produces a buildup of acids in the bloodstream called ketones,
eventually leading to diabetic ketoacidosis if untreated.
Diabetic complications
 Macrovascular disease
 The hallmark of diabetic macrovascular disease is accelerated
atherosclerosis affecting the aorta and large and medium-sized arteries.
 Myocardial infarction, caused by atherosclerosis of the coronary arteries
is the most common cause of death in diabetics
 Gangrene of the lower extremities, as a result of advanced vascular
disease (diabetic foot)
 The larger renal arteries also are subject to severe atherosclerosis, but
the most damaging effect of diabetes on the kidneys is exerted at the
level of the glomeruli and the microcirculation
 Hyaline arteriolosclerosis, the vascular lesion associated with
hypertension , is both more prevalent and more severe in diabetics than in
nondiabetics ´ It takes the form of an amorphous, hyaline thickening of
the wall of the arterioles, which causes narrowing of the lumen
 Microangiopathy4
 One of the most consistent morphologic features of diabetes is diffuse
thickening of basement membranes. The thickening is most evident
in the capillaries of the skin, skeletal muscle, retina, renal
glomeruli, and renal medulla.
 the basal lamina separating parenchymal or endothelial cells from the
surrounding tissue is markedly thickened by concentric layers of hyaline
material composed predominantly of type IV collagen . Of note, despite
the increase in the thickness of basement membranes, diabetic
capillaries are more leaky than normal to plasma proteins.
 The microangiopathy underlies the development of diabetic nephropathy,
retinopathy, and some forms of neuropathy.

PAS stain (periodic acid-schiff –PAS-)

4:excess glucose in blood will cause non-enzymatic combination between glucose

and proteins and formation of something called “Advanced Glycosylation End
products “ . Those AGEs will cross link with collagen and cause the microvascular
complications .
Nephropathy

 Renal failure is second only to myocardial infarction as a cause of death

from this disease.
Three lesions are encountered:
I. glomerular lesions
II. renal vascular lesions, principally arteriolosclerosis
III.pyelonephritis, including necrotizing papillitis.
 The most important glomerular lesions are capillary basement membrane
thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis.
 The glomerular capillary basement membranes are thickened along their
entire length.
 Diffuse mesangial sclerosis (hyaline fibrosis) consists of a diffuse
increase in mesangial matrix along with mesangial cell . When
glomerulosclerosis becomes marked, patients manifest the nephrotic
syndrome, characterized by proteinuria, hypoalbuminemia, and edema.
 Nodular glomerulosclerosis : ball-like deposits of a laminated matrix
situated in the periphery of the glomerulus . These nodules are PAS-
positive . This distinctive change has been called the Kimmelstiel-
Wilson lesion.
 Nodular glomerulosclerosis is encountered in approximately 15% to 30%
of persons with long-term diabetes. It is essentially pathognomonic of
diabetes.
 Both the diffuse and the nodular forms of glomerulosclerosis induce
sufficient ischemia to cause scarring of the kidneys, manifested by a
finely granular-appearing cortical surface
Occular Complications of Diabetes
 The ocular involvement may take the form of retinopathy, cataract
formation, or glaucoma. Retinopathy7, the most common pattern .

The lesion in the retina takes two forms:

 nonproliferative (background) retinopathy:
(related to the endothelial dysfunction)
Haemorrhages (due to the leaky basement-membrane), retinal exudates
(cotton wool spots5), microaneurysms, edema, thickening of the retinal
capillaries (microangiopathy).
The microaneurysms are discrete saccular dilations of retinal choroidal
capillaries that appear through the ophthalmoscope as small red dots.

 proliferative retinopathy:
It is a process of neovascularization6 and fibrosis.
This lesion leads to serious consequences, including blindness, especially
if it involves the macula and retinal detachment

5:Cotton wool spots are an abnormal finding on funduscopic exam of the retina of the
eye. They appear as fluffy white patches on the retina.
6: Neovascularization is the natural formation of new blood vessels (neo- + vascular + -
ization).
7: People with diabetes can have an eye disease called diabetic retinopathy. This is when
high blood sugar levels cause damage to blood vessels in the Retina. These blood vessels
can swell and leak. Or they can close, stopping blood from passing through. Sometimes
abnormal new blood vessels grow on the retina. All of these changes can steal your vision.
Diabetic Neuropathy: may be sensory or autonomic

 The central and peripheral nervous systems are not spared by

diabetes.
 The most frequent pattern of involvement is that of a peripheral,
symmetric neuropathy of the lower extremities affecting both motor
and sensory function, particularly the latter.
 Other forms include autonomic neuropathy, which produces
disturbances in bowel and bladder function and diabetic
mononeuropathy, which may manifest as sudden footdrop or wristdrop.
 Microvasculopathy involving the small blood vessels of nerves contributes
to the disorder.
 In a person with diabetic neuropathy, a trivial
 infection in a toe may be the first event in a long succession of
complications (gangrene, bacteremia, pneumonia) that may ultimately
lead to death
 Both hand and legs are affected “gloves and stocking” mostly starts with
the lower limbs.
 diagnosed with a pin-prick test.

Infections:
 Diabetic patients have an enhanced susceptibility to infections of the
skin, as well as to tuberculosis, pneumonia, and pyelonephritis.
 Such infections cause about 5% of diabetes-related deaths.
 Bacterial and Fungal Infections Occur in Diabetic Hyperglycemia if
Poorly Controlled.
 Renal papillary necrosis may be a devastating complication of bladder
infection.
 Mucormycosis: A dangerous infectious complication of poorly controlled
diabetes is often fatal fungal infection tends to originate in the
nasopharynx or paranasal sinuses and spreads rapidly to the orbit and
brain.
Gestational diabetes the infant is large in size, early delivery is recommended

 Diabetes Occurring During Pregnancy

 May Put both Mother and Fetus at risk
 Develops in only a few percent of seemingly healthy women
during pregnancy.
 It may continue after parturition in a small proportion of these
patients.
 These women highly susceptible to overt T2DM later in life.
summary
Definition : group of metabolic disorders characterized by hyperglycemia due to defect in insulin
secretion ,action or both
prediabetes > 140 ) 200 > ) Diagnosis : * random blood glucose
prediabetes > 110 ) 126 > ) * fasting glucose 126 mg/dL
OGTT *

type II type I types

relative deficiency absolute deficiency plasma insulin

to 90% 80% 10% prevalence

adulthood childhood and adolescence onset

multifactorial disease characterized autoimmune destruction of beta cells
by: insulin resistance + inadequate mediated by : autoantibodies + T cells pathogenesis
insulin secretion
genetic factor
diabetogenic” genes“ HLA-DR3, or DR4
- complex -
sedentary lifestyle + dietary habits infection environmental

Amyloid replacement of islets Reduction in the number and size of islets morphology
+ Leukocyte infiltration of the islets
polyuria ,polydipsia , obesity and polyuria, polydipsia, polyphagia ,weight manifestations
hyperosmolar non- ketotic coma .loss and diabetic ketoacidosis
complications

atherosclerosis affecting the aorta and large and medium-sized arteries,EX : * Macrovascular
. in coronary arteries → MI or in lower extremities vessels → Gangrene diseases
. - Hyaline arteriosclerosis - usually associated with hypertension *
.diffuse thickening of basement membranes * Microangiopathy
.diabetic capillaries are more leaky *
has a role in diabetic nephropathy, retinopathy, and some forms of *
.neuropathy
* glomerular lesions: Nephropathy
- capillary basement membrane thickening.
- diffuse mesangial sclerosis
- nodular glomerulosclerosis with ( Kimmelstiel-Wilson lesion ) change
* renal vascular lesions, principally arteriolosclerosis
*pyelonephritis, including necrotizing papillitis.
 Proliferative retinopathy Nonproliferative retinopathy

→ neovascularization and fibrosis hemorrhages, -retinal exudates -

(cotton wool spots), :ocular
retinal detachment → blindness retinopathy*
microaneurysms (small red dots
by ophthalmoscope) *cataract
edema, -thickening of the - , glaucoma*
retinal capillaries
.(microangiopathy)

autonomic nerves motor and sensory nerves

Neuropathy
disturbances in bowel and bladder peripheral, symmetric neuropathy
function of the lower extremities
Renal papillary necrosis as a complication of bladder infection * infection (bacteria
Mucormycosis* or fungi)

Gestational diabetes MODY

During Pregnancy* loss-of-function mutations within a single *
both Mother and Fetus at risk* .gene
Develops in only a few percent of seemingly * .resembles type 2 diabetes*
healthy women during pregnancy occurrence in younger patients*
may continue after parturition *
These women highly susceptible to overt *
T2DM later in life