Diabetes

Management and treatment

Dr. Ghulam Jilany Khan
Ph. D Pharmacology
As Exocrine gland secrets Pancreatic juice into pancreatic duct
As endocrine gland secrets hormones (insulin, glucagon)
What is diabetes?
 Diabetes mellitus (DM) is a group of diseases characterized
by high levels of blood glucose resulting from defects in
insulin production, insulin action, or both.

 The term diabetes mellitus describes a metabolic disorder

of multiple aetiology characterized by chronic
hyperglycaemia with disturbances of carbohydrate, fat and
protein metabolism resulting from defects in insulin
secretion, insulin action, or both.

 The effects of diabetes mellitus include long–term

damage, dysfunction and failure of various organs.
 Never get confused with…
Diabetes insipidus (DI)
• Diabetes insipidus (DI) is a condition characterized by large amounts of dilute
urine and increased thirst. The amount of urine produced can be nearly 20 liters
per day. Reduction of fluid has little effect on the concentration of the urine.
Complications may include dehydration or seizures.
• There are four types of DI, each with a different set of causes. 
1. Central DI (CDI) is due to a lack of the hormone vasopressin (antidiuretic
hormone).This can be due to damage to the hypothalamus or pituitary
gland or genetics
2. Nephrogenic diabetes insipidus (NDI) occurs when the kidneys do not respond
properly to vasopressin.
3. Dipsogenic DI is due to abnormal thirst mechanisms in the hypothalamus
4. Gestational DI occurs only during pregnancy 
• Diagnosis is often based on urine tests, blood tests, and the fluid deprivation test. 
Diabetes mellitus is a separate condition with an unrelated mechanism, though both
can result in the production of large amounts of urine.
Diabetes mellitus (DM)
Commonly referred to as diabetes, is a group of
metabolic disorders in which there are high blood
sugar levels over a prolonged period. Symptoms of
high blood sugar include frequent urination,
increased thirst, and increased hunger.
Diabetes Long-term Effects
 The long–term effects of diabetes mellitus include
progressive development of the specific complications
of retinopathy with potential blindness, nephropathy
that may lead to renal failure, and/or neuropathy with
risk of foot ulcers, amputation, Charcot joints, and
features of autonomic dysfunction, including sexual
dysfunction.

 People with diabetes are at increased risk of

cardiovascular, peripheral vascular and
cerebrovascular disease.
 Types of Diabetes
• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus
• Gestational Diabetes
• Other types:
LADA
MODY (maturity-onset diabetes of youth)
Secondary Diabetes Mellitus
Type 1 diabetes
 Was previously called insulin-dependent diabetes mellitus
(IDDM) or juvenile-onset diabetes.
 Type 1 diabetes develops when the body’s immune system
destroys pancreatic beta cells, the only cells in the body that
make the hormone insulin that regulates blood glucose.
 This form of diabetes usually strikes children and young
adults, although disease onset can occur at any age.
 Type 1 diabetes may account for 5% to 10% of all diagnosed
cases of diabetes.
 Risk factors for type 1 diabetes may include autoimmune,
genetic, and environmental factors.
Type 2 diabetes
 Was previously called non-insulin-dependent diabetes mellitus
(NIDDM) or adult-onset diabetes.
 Type 2 diabetes may account for about 90% to 95% of all diagnosed
cases of diabetes.
 It usually begins as insulin resistance, a disorder in which the cells do
not use insulin properly. As the need for insulin rises, the pancreas
gradually loses its ability to produce insulin.
 Type 2 diabetes is associated with older age, obesity, family history of
diabetes, history of gestational diabetes, impaired glucose metabolism,
physical inactivity, and race/ethnicity.
 African Americans, Hispanic/Latino Americans, American Indians, and
some Asian Americans and Native Hawaiians or Other Pacific Islanders
are at particularly high risk for type 2 diabetes.
 Type 2 diabetes is increasingly being diagnosed in children and
adolescents.
Gestational diabetes
 A form of glucose intolerance that is diagnosed in some
women during pregnancy.
 Gestational diabetes occurs more frequently among African
Americans, Hispanic/Latino Americans, and American Indians.
It is also more common among obese women and women with
a family history of diabetes.
 During pregnancy, gestational diabetes requires treatment to
normalize maternal blood glucose levels to avoid complications
in the infant.
 After pregnancy, 5% to 10% of women with gestational
diabetes are found to have type 2 diabetes.
 Women who have had gestational diabetes have a 20% to 50%
chance of developing diabetes in the next 5-10 years.
Other types of DM
• Other specific types of diabetes result from
specific genetic conditions (such as maturity-onset
diabetes of youth), surgery, drugs, malnutrition,
infections, and other illnesses.

• Such types of diabetes may account for 1% to 5%

of all diagnosed cases of diabetes.
LADA
 Latent Autoimmune Diabetes in Adults (LADA) is a
form of autoimmune (type 1 diabetes) which is
diagnosed in individuals who are older than the usual
age of onset of type 1 diabetes.
 Alternate terms that have been used for "LADA"
include Late-onset Autoimmune Diabetes of
Adulthood, "Slow Onset Type 1" diabetes, and
sometimes also "Type 1.5
 Often, patients with LADA are mistakenly thought to
have type 2 diabetes, based on their age at the time
of diagnosis.
 LADA (cont.)

Pancreatic islet-cell antibodies (ICA) are

important markers for two subtypes of
Glutamic acid decarboxylase
insulin-dependent diabetes mellitus and
stain the entire islet in the standard
The human leukocyte antigen (HLA)
immunofluorescence test. This could
system or complex is a gene complex
indicate either a mixture of antibodies each
encoding the major histocompatibility
directed against one cell type, or a
complex (MHC) proteins in humans.
population of antibodies reacting with a
These cell-surface proteins are
single antigen common to the endocrine
responsible for the regulation of the
pancreas.
LADA (cont.)
• About 80% of adults apparently with recently
diagnosed Type 2 diabetes but with GAD auto-
antibodies (i.e. LADA) progress to insulin
requirement within 6 years.

• The potential value of identifying this group at high

risk of progression to insulin dependence includes:
• the avoidance of using metformin treatment
• the early introduction of insulin therapy
MODY
 MODY – Maturity Onset Diabetes of the Young

 MODY is a monogenic form of diabetes with an autosomal dominant

mode of inheritance:
◦ Mutations in any one of several transcription factors or in the enzyme
glucokinase lead to insufficient insulin release from pancreatic ß-cells, causing
MODY.
◦ Different subtypes of MODY are identified based on the mutated gene.

 Originally, diagnosis of MODY was based on presence of non-ketotic

hyperglycemia in adolescents or young adults in conjunction with a
family history of diabetes.

 However, genetic testing has shown that MODY can occur at any age
and that a family history of diabetes is not always obvious.
MODY (cont.)

a very rare, generally severe form of neonatal diabetes mellitus (NDM)

characterized by a triad of developmental delay, epilepsy, and neonatal diabetes.
MODY (cont.)
 Within MODY, the different subtypes can essentially
be divided into 2 distinct groups: glucokinase MODY
and transcription factor MODY, distinguished by
characteristic phenotypic features and pattern on oral
glucose tolerance testing.

 Glucokinase MODY requires no treatment, while

transcription factor MODY (i.e. Hepatocyte nuclear
factor -1alpha) requires low-dose sulfonylurea
therapy and PNDM (caused by Kir6.2 mutation)
requires high-dose sulfonylurea therapy.
Secondary DM
Secondary causes of Diabetes mellitus include:

 Acromegaly,
 Cushing syndrome,
 Thyrotoxicosis,
 Pheochromocytoma
 Chronic pancreatitis,
 Cancer
 Drug induced hyperglycemia:
◦ Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin
resistance.
◦ Beta-blockers - Inhibit insulin secretion.
◦ Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium release.
◦ Corticosteroids - Cause peripheral insulin resistance and gluconeogensis.
◦ Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels.
◦ Naicin - They cause increased insulin resistance due to increased free fatty acid mobilization.
◦ Phenothiazines - Inhibit insulin secretion.
◦ Protease Inhibitors - Inhibit the conversion of proinsulin to insulin.
◦ Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased insulin
resistance due to increased free fatty acid mobilization.
Prediabetes: Impaired glucose
tolerance and impaired fasting glucose
Prediabetes is a term used to distinguish people who are at
increased risk of developing diabetes. People with prediabetes
have impaired fasting glucose (IFG) or impaired glucose
tolerance (IGT). Some people may have both IFG and IGT.

IFG is a condition in which the fasting blood sugar level is

elevated (100 to 125 milligrams per decilitre or mg/dL) after an
overnight fast but is not high enough to be classified as
diabetes.

IGT is a condition in which the blood sugar level is elevated

(140 to 199 mg/dL after a 2-hour oral glucose tolerance test),
but is not high enough to be classified as diabetes.
 Prediabetes: Impaired glucose tolerance and impaired
fasting glucose (cont.)
• Progression to diabetes among those with prediabetes is not
inevitable. Studies suggest that weight loss and increased
physical activity among people with prediabetes prevent or
delay diabetes and may return blood glucose levels to normal.

• People with prediabetes are already at increased risk for other

adverse health outcomes such as heart disease and stroke.
 Assessment
• History
• Blood tests:
• Fasting plasma glucose (FPG)
• Oral glucose tolerance test (OGTT)
• Other blood tests for diabetes
• Screening for diabetes
• Ongoing assessment—
• glycosylated hemoglobin assays(HbA1c),
• glycosylated serum proteins and albumin,
• urine tests
• tests for renal function-GFR
 Acute Complications of Diabetes
• Diabetic ketoacidosis

• Hyperglycemic-hyperosmolar state (HHS)

• Hypoglycemia from too much insulin or too little

glucose
 Chronic Complications of
Diabetes
• Macrovascular and microvascular disease

• Retinopathy (vision problems)

• Nephropathy (kidney dysfunction)

• Neuropathy (nerve dysfunction)

 Macrovascular Complications
• Cardiovascular disease

• Cerebrovascular disease
 Microvascular Complications
• Eye and vision complications

• Diabetic neuropathy

• Diabetic nephropathy

• Male erectile dysfunction

 Type 2 Diabetes and Metabolic
Syndrome
• Metabolic syndrome, also called syndrome X, is
classified as the simultaneous presence of metabolic
factors known to increase risk for developing type 2
diabetes and cardiovascular disease.
Drug Therapy usually for
NIDDM
• SULFONYLUREAS • THIAZOLIDINEDIONES
• Glipizide • Pioglitazone

• Glyburide • Rosiglitazone

• Glimepiride • GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-

• GLITINIDES 1) RECEPTOR AGONISTS

• Repaglinide • Exenatide

• Nateglinide • DIPEPTIDYL PEPTIDASE-4 (DPP-4)

• BIGUANIDES INHIBITORS
• Sitagliptin
• Metformin
• AMYLIN ANALOG
• ALPHA-GLUCOSIDASE INHIBITORS
• Pramlintide
• Acarbose,
• BILE ACID SEQUESTRANT
• Miglitol
 Insulin Therapy
• Types of insulin
• Rapid
• Short
• Intermediate
• Long

• Insulin regimens

• Factors influencing insulin absorption

• Mixing insulin
 Potential for Hypoglycemia
• Blood glucose level <70 mg/dL
• Diet therapy—carbohydrate replacement
• Drug therapy—glucagon, 50% dextrose, diazoxide,
octreotide
• Prevention strategies for:
• Insulin excess
• Deficient food intake
• Exercise
• Alcohol
 Complications of Insulin Therapy
• Lipoatrophy (the localized loss of fat tissue. This may occur as a result of subcutaneous injections of
insulin in the treatment of diabetes, from the use of Human Growth Hormone or from subcutaneous injections
of Copaxone used for the treatment of multiple sclerosis.)
• Lipohypertrophy (a lump under the skin caused by accumulation of extra fat at the site of many
subcutaneous injections of insulin. It may be unsightly, mildly painful, and may change the timing or
completeness of insulin action.)
• Dawn phenomenon (sometimes called the dawn effect, is an early-morning (usually
between 2 a.m. and 8 a.m.) increase in blood sugar (glucose) which occurs to some extent in all humans, more
relevant to people with diabetes.)
• Somogyi’s phenomenon (elevated blood sugars in the morning. Also called
the Somogyi effect and posthypoglycemic hyperglycemia, it is a rebounding high blood sugar that is a response
to low blood sugar.)
 Care with DM
• Foot injury is the most common complication of
diabetes leading to hospitalization

• Prevention of high-risk conditions

• Peripheral sensation management

• Footwear

• Foot care
Hammertoe
Testing Sensation
 Wound Care
• Wound environment

• Débridement

• Elimination of pressure

• Growth factors
 Chronic Pain
• Neuropathic pain results from damage to the nervous
system anywhere along the nerve
• Pharmacologic agents
• Nonpharmacologic interventions
Drug Therapy usually for
NIDDM
• SULFONYLUREAS
• Glipizide
• Glyburide
• Glimepiride
• GLITINIDES
• Repaglinide
• Nateglinide
• BIGUANIDES
• Metformin
• ALPHA-GLUCOSIDASE INHIBITORS
• Acarbose,
• Miglitol
• THIAZOLIDINEDIONES
• Pioglitazone
• Rosiglitazone
• GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS
• Exenatide
• DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
• Sitagliptin
• AMYLIN ANALOG
• Pramlintide
• BILE ACID SEQUESTRANT
• Colesevelam hydrochloride
 Insulin is a small protein consisting of an A
A chain chain of 21 amino acids linked by two disulfide
(S—S) bridges to a B chain of 30 amino acids.

Beta cells have channels in their plasma

membrane that serve as glucose
detectors. Beta cells secrete insulin in
response to a rising level of circulating
glucose.
B chain
Insulin affects many organs:
amino acids protein
uptake synthesis
• It stimulates skeletal muscle fibers.

• It stimulates liver cells. glycogen

glucose
synthesis
uptake
• It acts on fat cells
fat
synthesis
• It inhibits production of certain
enzyme.
enzyme glycogen
In each case, insulin triggers production breaking
these effects by binding to the
insulin receptor.
 The insulin receptor (IR) is a
transmembrane glycoprotein,
composed of 2α and 2β domains.
.

Its intracellular tyrosine kinase

domain is activated by binding of
insulin, leading to a cascade of
signaling events.
Who need insulin medicine
• Type I (insulin dependent) diabetes patients whose body
produces no insulin.
• Type 2 diabetes patients that do not always produce enough
insulin.

Treatment

 subcutaneous injection
Insulin drug evolution
Stage 1 Insulin was extracted from the glands of
cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin by

removing the one amino acid that distinguishes them
and replacing it with the human version.
• Stage 3 Insert the human insulin
gene into E. coli and culture the
recombinant E.coli to produce
insulin (trade name = Humulin®).
Yeast is also used to produce
insulin (trade name =
Novolin®) (1987).

Recombinant DNA technology has also made it possible to

manufacture slightly-modified forms of human insulin that
work faster (Humalog® and NovoLog®) or slower
(Lantus®) than regular human insulin.
Types of insulin

• Regular insulins

• Insulin analogs

• Pre-mixed insulin

Short peptide mimics

Regular insulins:

• Human insulin: Humulin® (from E.coli),

Novalin® (from yeast)
• NPH - neutral protamine Hagedorn (NPH),
protamine mixed.
• Lente® insulin / Ultralente® insullin-
zinc added
Types of insulin

• Regular insulins

• Insulin analogs

• Pre-mixed insulin

Short peptide mimics

Insulin Analogs:

• Fatty Acid Acylated insulins

• Insulin Lispro (Humalog®) (1996)

• Insulin Aspart (NovoLog®) (2000)

• Insulin Glargine (Lantus®) (2002)

• Insulin Detemir (Levemir®) (Jun.,2005)

• Insulin Glulisine (Apidra®) (Jan., 2006)

 Amino Acid Substitutons
A- B- chain Position
chai
n
Position
Source/ A21 B3 B28 B29 B30 B31
Type And
B32
Human Asn Asn Pro Lys Thr

Aspart Asn Aspartic Lys Thr

acid
Lispro Asn Lys Pro Thr
Glulisin Asn Lys Pro Glu Thr rapid-acting
e
Glargine Gly Pro Lys Thr Arg

Detemir Lys Myristic

acid long-acting