Diabetes Mellitus

Dept. of Pharmacology, GMC 1

Amritsar

What is Diabetes Mellitus?

• Diabetes mellitus is a group of metabolic
diseases characterized by high blood
glucose levels – Hyperglycaemia
• This results from defects in insulin
secretion, or action, or both.
• Hyperglycemia lead to spillage of glucose
into the urine, hence the term Diabetes -
sweet urine.

Dept. of Pharmacology, GMC 2

Amritsar
• Normally, blood glucose levels are tightly
controlled by insulin, a hormone produced by the
β cells in the pancreas.
• Whenever there is an elevation of blood glucose
insulin is released from the pancreas to
normalize the glucose level.
• In patients with diabetes mellitus, the absence or
insufficient production of insulin causes
hyperglycemia.

Dept. of Pharmacology, GMC 3

Amritsar

Dept. of Pharmacology, GMC 4

Amritsar
 Impact of Diabetes
• Diabetes mellitus is a chronic medical condition,
meaning it can last a lifetime
• Long standing untreated diabetes mellitus can
lead to blindness, kidney failure, and nerve
damage.
• Diabetes mellitus is also an important factor in
accelerating the progress of atherosclerosis,
leading to strokes, coronary heart diseases, and
other blood vessel diseases.
• Diabetes mellitus is predicted to become the
leading cause of morbidity and death in the
coming decade.
Dept. of Pharmacology, GMC 5
Amritsar

Types of diabetes mellitus

• There are two major types of diabetes mellitus,
called type 1 and type 2.
• Type 1 diabetes mellitus (previously called
insulin dependent diabetes mellitus [IDDM], or
juvenile onset diabetes mellitus.)
• In type 1 diabetes mellitus, the pancreas
undergoes an autoimmune attack by the body
itself, and is rendered incapable of making
insulin.
• The patient with type 1 diabetes must rely on
exogenously administered insulin for survival.

Dept. of Pharmacology, GMC 6

Amritsar
 Type 2 DM
• Type 2 diabetes mellitus (previously referred to as non-
insulin dependent diabetes mellitus (NIDDM])
• In type 2 diabetes, patients can still produce insulin, but
it is Insufficient-either absolutely or relative to the body's
needs.
• A major feature of type 2 diabetes is a lack of sensitivity
to insulin by the cells of the body (particularly fat and
muscle cells)-Insulin resistance.
• The release of insulin by the pancreas may also be
defective, and occur late in response to increased
glucose levels.
• Finally, the liver in these patients continues to produce
glucose despite elevated glucose levels

Dept. of Pharmacology, GMC 7

Amritsar

• The three basic pathophysiological

abnormalities are:
• impaired insulin secretion
• excessive hepatic glucose production
• insulin resistance in
– skeletal muscle
– liver and
– adipose tissue
Dept. of Pharmacology, GMC 8
Amritsar
 Secondary Diabetes
• Secondary diabetes mellitus develops when the
pancreatic tissue responsible for the production of insulin
is absent because it is destroyed by disease, such as
– chronic pancreatitis
– trauma
– surgical removal of the pancreas.
• Diabetes can also result from other hormonal
disturbances,
– Acromegaly
– Cushing's syndrome.
• Certain medications may worsen diabetes control, or
"unmask" latent diabetes.
– steroids
– estrogen

Dept. of Pharmacology, GMC 9

Amritsar

Symptoms
• The early symptoms of untreated diabetes mellitus are
related to elevated blood sugar levels, and loss of
glucose in the urine.
• High amounts of glucose in the urine can cause
increased urine output and lead to dehydration.
– increased thirst and water consumption.
• The inability to utilize glucose energy eventually leads to
weight loss despite an increase in appetite.
• Patients with diabetes are prone to developing infections
of the bladder, skin, and vaginal areas.
• Fluctuations in blood glucose levels can lead to blurred
vision. Extremely elevated glucose levels can lead to
lethargy and coma (diabetic coma).

Dept. of Pharmacology, GMC 10

Amritsar
 Common Symptoms
• Frequent urination (polyuria)
• Excessive thirst (polydipsia)
• Extreme hunger (polyphagia)
• Unexplained weight loss
• Increased fatigue
• Irritability
• Blurry vision
• Slow–healing sores
• Frequent infections
• Dry, itchy skin
• Numbness or tingling in hands or feet
• Red, swollen or tender gums
Dept. of Pharmacology, GMC 11
Amritsar

Diagnosis
• The fasting blood glucose test is the preferred way to
diagnose diabetes.
• After the person has fasted overnight (at least 8 hours),
a single sample of blood is drawn and analysed.
• Normal fasting plasma glucose levels are less than 110
milligrams per deciliter (mg/dl).
• Fasting plasma glucose levels of more than 126 mg/dl
on two or more tests on different days indicate diabetes.
• If the overnight fasting blood glucose is greater than 126
mg/dl on two different tests on different days, the
diagnosis of diabetes mellitus is made.
• When fasting a blood glucose stays above 110 mg/dl,
but in the range of 110-126mg/dl, this is known as
impaired fasting glucose (IFG).
Dept. of Pharmacology, GMC 12
Amritsar
 Discovery of Insulin
• University of Toronto in 1921-22
• Physician Frederick Banting, graduate student
Charles Best, Professor of Physiology J.J.R.
Macleod, and biochemist J.B. Collip.
• Fourteen-year-old Leonard Thompson was the
first patient on whom insulin therapy was used.
• 1923 Nobel Prize in Physiology and Medicine -
Banting and Macleod.

Dept. of Pharmacology, GMC 13

Amritsar

Insulin
• Insulin is produced in the beta cells of the
pancreatic islets.
• It is initially synthesized as a single-chain 86-
amino-acid precursor polypeptide, preproinsulin.
• Subsequent proteolytic processing removes the
amino terminal signal peptide, giving rise to
proinsulin.
• Proinsulin is structurally related to insulin-like
growth factors I and II, which bind weakly to the
insulin receptor.

Dept. of Pharmacology, GMC 14

Amritsar
 Insulin Biosynthesis

Dept. of Pharmacology, GMC 15

Amritsar

• Cleavage of an internal 31-residue fragment

from proinsulin generates the C peptide and the
A (21 amino acids) and B (30 amino acids)
chains of insulin, which are connected by
disulfide bonds.
• The mature insulin molecule and C peptide are
stored together and co-secreted from secretory
granules in the beta cells.
• Because the C peptide is less susceptible than
insulin to hepatic degradation, it is a useful a
marker of insulin secretion and allows
discrimination of endogenous and exogenous
sources of insulin in the evaluation of
hypoglycemia.
Dept. of Pharmacology, GMC 16
Amritsar
 Insulin-Structure
B- Chain

A Chain

Dept. of Pharmacology, GMC 17

Amritsar

Regulation of Insulin Secretion

• Glucose is the key regulator of insulin secretion
by the pancreatic beta cell
• Amino acids, ketones, various nutrients,
gastrointestinal peptides, and neurotransmitters
also influence insulin secretion.
• Glucose levels < 70 mg/dL stimulate insulin
synthesis. Glucose stimulates insulin secretion
through a series of regulatory steps that begin
with transport into the beta cell by the GLUT2
glucose transporter.

Dept. of Pharmacology, GMC 18

Amritsar
 Insulin and Carbohydrates
• Influences glucose metabolism in most
tissues.
• Liver
– Inhibits glycogenolysis
– Inhibits gluconeogenesis
– Stimulates glycogen synthesis
– Increases glucose utilization- glycolysis
• Overall effect is to increase glycogen
stores
Dept. of Pharmacology, GMC 19
Amritsar

Other Tissues
• Muscles:
– Glucose uptake is slow
– Insulin increase facilitated transport of glucose via
Glut – 4 transporter
– Stimulates glycogen synthesis and glycolysis
• Adipose tissue:
– Increases glucose uptake via Glut-4
– Glycerol is formed that esterifies with fatty acids to
form triglycerides.
• Insulin slows the breakdown of protein for
glucose production (gluconeogenesis).
Dept. of Pharmacology, GMC 20
Amritsar
 Kinetics
• Pancreas secretes 40ug insulin/ hr
• Once insulin is secreted into the portal vein,
~50% is removed and degraded by the liver.
• Half life is 5-6 minutes.
• The remaining insulin enters the systemic
circulation and binds to its receptor in target
sites.
• The insulin receptor belongs to the tyrosine
kinase class of membrane-bound receptors.
Dept. of Pharmacology, GMC 21
Amritsar

• Insulin binding to the receptor

– stimulates intrinsic tyrosine kinase activity Æ leading
to receptor autophosphorylation and the recruitment
of intracellular signaling molecules, such as insulin
receptor substrates (IRS) 1 and 2.
• These and other adaptor proteins initiate a
complex cascade of phosphorylation and
dephosphorylation reactions, ultimately resulting
in the widespread metabolic and mitogenic
effects of insulin.
• Activation of other insulin receptor signaling
pathways induces glycogen synthesis, protein
synthesis, lipogenesis, and regulation of various
genes in insulin-responsive cells.
Dept. of Pharmacology, GMC 22
Amritsar
 Consequences of Hyperglycaemia
• Hyperglycaemia (random blood glucose concentration
more than 200 mg/dL) results when insulin deficiency
leads to uninhibited gluconeogenesis and prevents the
use and storage of circulating glucose.
• The kidneys cannot reabsorb the excess glucose load,
causing glycosuria, osmotic diuresis, thirst, and
dehydration.
• Increased fat and protein breakdown leads to ketone
production and weight loss.
• Without insulin, a type 1 diabetic wastes away and
eventually dies from diabetic ketoacidosis (DKA)

Dept. of Pharmacology, GMC 23

Amritsar

Dept. of Pharmacology, GMC 24

Amritsar
 Sources of Insulin
• Synthesised and stored in granules in the
β islet cells of the pancreas.
• Basic structure is similar in all animal
species with minor differences.
• Bovine insulin is different by three amino
acids and is antigenic.
• Porcine insulin is different by one amino
acid and is less antigenic.
Dept. of Pharmacology, GMC 25
Amritsar

Human Insulin
• Made by
– enzyme modification of Porcine insulin
– Recombinant DNA technique
• Major forms of human insulin:
– Enzyme Modified Porcine – emp
– Proinsulin Recombinant in Bacteria- prb
– Precursor Insulin Yeast Recombinant- pyr

Dept. of Pharmacology, GMC 26

Amritsar
• Insulin is inactivated by gastro-intestinal
enzymes, thus given by injection

• The subcutaneous route is ideal.

• It is usually injected into the upper arms,

thighs, buttocks, or abdomen

Dept. of Pharmacology, GMC 27

Amritsar

Dept. of Pharmacology, GMC 28

Amritsar
 Indications for Insulin
• Insulin is needed by all patients with type 1
diabetes
• Emergency treatment of ketoacidosis.
• In type 2 diabetes for intercurrent events
surgery, infections, serious illness, trauma.
• During pregnancy.
• Emergency treatment of hyperkalaemia to
lower extracellular K+
Dept. of Pharmacology, GMC 29
Amritsar

Types of Insulin Preparations

• those of short duration which have a relatively
rapid onset of action, namely soluble insulin,
insulin lispro and insulin aspart;
• those with an intermediate action, e.g. isophane
insulin and insulin zinc suspension; and
• those whose action is slower in onset and lasts
for long periods, e.g. crystalline insulin zinc
suspension.
• Biphasic Insulins-mixture of two different
insulins.

Dept. of Pharmacology, GMC 30

Amritsar
 Rapid
• Onset: 10–15 min
• Peak: 60–90 min
• Duration: 4 – 5 h
• Regular Soluble –crystalline
• Insulin lispro reversal of the proline at B-28 and
the lysine at B-29
• Insulin aspart : proline replaced by aspartic acid
at B-28
• Insulin glulisine: lysine at B-29 replaced by
glutamic acid
Dept. of Pharmacology, GMC 31
Amritsar

Fast acting
• Fast-acting (clear)

• Onset: 0.5–1 h

• Peak: 2–4 h

• Duration: 5–8 h

Dept. of Pharmacology, GMC 32

Amritsar
 Intermediate-acting

• Onset: 1–3 h
• Peak: 5–8 h
• Duration: up to 18 h
• NPH(isophane)
• Lente

Dept. of Pharmacology, GMC 33

Amritsar

Long-acting-Slow
• Onset: 3–4 h
• Peak: 8–15 h
• Duration: 22–26 h
• Ultralente
• Protamine zinc

Dept. of Pharmacology, GMC 34

Amritsar
 Extended long-acting
• Onset: 90 min
• Duration:24 h
• Insulin glargine: aspargine at A-21
replaced by glycine and two arginines to C
terminus of B chain

Dept. of Pharmacology, GMC 35

Amritsar

Mixtures/ Biphasic Insulins

• Mixture of Regular and NPH insulins
• 20/80
• 30/70
• 40/60
• 50/50
• 25 Lispro/ 75 NPH
• 50 Lispro/ 50 NPH

Dept. of Pharmacology, GMC 36

Amritsar
 Dept. of Pharmacology, GMC 37
Amritsar

Units
• One unit=the amount of insulin required to
reduce the blood glucose in a fasting rabbit to 45
mg/dL
• All commercial preparations are available in a
concentration of 100 units/ ml
• U-40 Insulins in a concentration of 40 Units/ml
• More concentrated solutions – 500 Units/ml are
available for resistant patients.

Dept. of Pharmacology, GMC 38

Amritsar
 Dept. of Pharmacology, GMC 39
Amritsar

Adverse Effects
• Hypoglycaemia
– Corrected by oral glucose, iv glucose or iv
glucagon
• Dawn Phenomenon
• Allergic reaction
• Lipodystrophy
• Lipohypertrophy
• Insulin oedema
Dept. of Pharmacology, GMC 40
Amritsar
 Dawn Phenomenon
• Refers to increased glucose production
and insulin resistance brought on by the
release of counterregulatory hormones in
the early morning hours near waking.
• Dawn phenomenon is variable and
manifests as either high fasting glucose
levels or an increased insulin requirement
to cover breakfast compared to equivalent
meals at other times of day.

Dept. of Pharmacology, GMC 41

Amritsar

Other Modalities
• Inhaled Insulin
• Nasal Insulin
• Subcutaneous pellets
• Islet Cell Transplants
• Gene therapy

Dept. of Pharmacology, GMC 42

Amritsar
 Pathophysiolgical
Considerations of Diabetes
• Insulin resistance
– ⇓ insulin receptor number
– ⇓ insulin receptor kinase activity
– Post-receptor defects
⇓ GLUT4 translocation from impaired signaling
• Impaired islet function
– Loss of first phase insulin secretion
– ⇑ secretion of proinsulin
– Defective pulsatile insulin secretion
– Deposition of islet amyloid polypeptide

Dept. of Pharmacology, GMC 43

Amritsar

Treatment Modalities
• Diet and exercise
– 80 % of Type 2 diabetics are obese
– ⇓ caloric intake
⇑ physical exercise
– first line of treatment
– recent clinical trial showed that exercising
at least 30 minutes a day reduces Type 2
diabetes risk more effectively than
medication

Dept. of Pharmacology, GMC 44

Amritsar
 Oral Drug Therapy for Type 2 DM

• Sulfonylureas
• Repaglinide
Nateglinide
} Insulin secretagogues

• Biguanides
• Thiazolidinediones } Insulin sensitizers

• Acarbose
Miglitol
} Inhibitors of CHO
absorption

Dept. of Pharmacology, GMC 45

Amritsar

Sulphonylureas
• First generation: • Second generation:
– Tolbutamide – Glibenclamide
– Acetohexamide (glyburide)
– Tolazamide – Glipizide
– Chlorpropamaide – Gliclazide
– Glimepiride
• Highly potent (x100)
• Safe on long term use

Dept. of Pharmacology, GMC 46

Amritsar
 Mechanism of Action
• Stimulate insulin release from pancreatic beta
cells-secretagogues.
• Reduce hepatic clearance of insulin
• On initial administration:
– Plasma insulin levels are increased
– Insulin secretion in response to glucose is
increased
• On prolonged use: circulating insulin levels
return to pretreatment levels but reduced blood
glucose levels are maintained.
Dept. of Pharmacology, GMC 47
Amritsar

• Potassium channel blockers whose effect on the

pancreatic β-islet cells is to allow an influx of
calcium into the cell, which causes increased
release of insulin.
• Other potential pancreatic effects include
– inhibition of glucagon release.
• Extrapancreatic mechanisms
– increasing insulin receptor binding affinity,
– increasing insulin's effect by a post-receptor
action
– decreasing hepatic insulin extraction.
Dept. of Pharmacology, GMC 48
Amritsar
 Sulfonylureas: Mechanism of Action

GLUT2 Na+
K+ - Sulfonylureas

Na+ KIR K+
K+
Vm
K+
Ca2+ -
Pancreatic Ca2+
Voltage-gated
ß cell Ca2+ channel
Ca2+

Insulin granules
Dept. of Pharmacology, GMC 49
Amritsar

Sulfonylureas: Mechanism of Action

Improved insulin sensitivity from improved
glucose control
Chronic treatment with sulfonylureas ⇒
improved FPG and OGT
unchanged or decreased basal insulin
unchanged or decreased stimulated insulin

•Normalization of glycemia results in

increased sensitivity to insulin
•Improved glucose control results in
increased ß cell responsiveness
Dept. of Pharmacology, GMC 50
Amritsar
 Pharmacokinetics
• Similar spectrum of activity
• All are absorbed from the GIT
– Food and hyperglycaemia retard absorption
• Highly plasma protein bound
• 2nd generation SUs have short half lives
(3-5 h)
• Hypoglycaemic effects last for 12-24 h ?
• Metabolised by liver
Dept. of Pharmacology, GMC 51
Amritsar

Uses
• To control hyperglycaemia in type 2
diabetes mellitus not managed by diet and
lifestyle changes.
• More effective in patients > 40 years.
• Overweight patients

Dept. of Pharmacology, GMC 52

Amritsar
 Contraindications
• Type 1 DM
• Pregnancy
• Lactation
• Hepatic &
• Renal insufficiency
• Severe infections
• Severe stress or trauma

Dept. of Pharmacology, GMC 53

Amritsar

Adverse Effects
• Hypoglycaemia: the longer the half life of the
agent the more likely it is to induce
hypoglycaemia.
• Displacement from binding sites by other drugs
can exacerbate hypoglycaemia.
• Nausea & vomiting, cholestatic jaundice,
agranulocytosis, aplastic & haemolytic anaemia,
hypersensitivity and severe skin reactions.
• Disulfiram like effect.
• Hyponatremia by potentiating effect of ADH on
collecting ducts-useful in Diabetes Insipidus.

Dept. of Pharmacology, GMC 54

Amritsar
 Therapeutic Status
• Clinical efficacy of sulfonylureas is related to the
pre-treatment levels of fasting plasma glucose
and HbA1C- the higher the fasting glucose level,
the greater the effect.
• In patients with a pre-treatment glucose level of
approximately 200 mg/dl sulfonylureas typically
reduce glucose by 60-70 mg/dl and HbA1C by
1.5-2%.
• The principal advantage of glimepiride and
glipizide compared to other agents is the once
daily dosing regimen.
• Primary as well as secondary failure is reported.
• Weight gain and CVS problems are not
remedied. Dept. of Pharmacology, GMC 55
Amritsar

Biguanides
• Metformin
• Phenformin – now withdrawn
• Antihyperglycaemic drug
• Does not cause insulin release
• Does not cause hypoglycaemia
• Decreases basal hepatic glucose production
• Activates AMP-activated protein kinase (AMPK)-
a major cellular regulator of lipid and glucose
metabolism.
• Increased action of insulin on muscle and fat.
• Decreased absorption of glucose from intestine.
Dept. of Pharmacology, GMC 56
Amritsar
 Contraindications
• Renal impairment
• Hepatic disease
• Alcoholics
• History of lactic acidosis
• Cardiac failure
• Hypoxic lung disease
• Pregnancy
• Children
Dept. of Pharmacology, GMC 57
Amritsar

Side effects
• Diarrhoea
• Abdominal discomfort
• Nausea
• Metallic taste
• Anorexia

Dept. of Pharmacology, GMC 58

Amritsar
• Metformin monotherapy reduces fasting plasma
glucose by 60-70 mg/dl (3.3-3.9 mmol/l) and
HbA1C by 1.5-2.0%- same as with SUs.
• Metformin also reduces fasting plasma insulin,
triglycerides, and free fatty acids.
• Unlike sulfonylurea treatment, metformin
monotherapy is not associated with weight gain
and even promotes weight loss, reduce the risk
of developing macrovascular complications.
• When added to a sulfonylurea, the effects of
both agents are additive, consistent with their
different mechanisms of action.
• Can also be combined with other oral agents
Dept. of Pharmacology, GMC 59
Amritsar

Thiazolidinediones
• Pioglitazone and Rosiglitazone
• Insulin sensitizing compounds
• Selective agonists for the peroxisome
proliferator-activated receptor gamma (PPAR-γ),
a member of the superfamily of nuclear hormone
receptors that function as ligand-activated
transcription factors.
• The PPAR family, functions as receptors for fatty
acids and their metabolites (e.g. eiconasoids)
and, consequently, plays a critical physiological
role the regulation of glucose, fatty acid, and
cholesterol metabolism.
Dept. of Pharmacology, GMC 60
Amritsar
 Dept. of Pharmacology, GMC 61
Amritsar

• Reduction of insulin resistance and improvement

of insulin sensitivity, resulting in a reduction of
fasting plasma glucose, insulin, and free fatty
acids.
• Exhibit a delay of 4-12 weeks in the onset of
their therapeutic benefits due to regulation of
gene expression.
• Beneficial in “metabolic syndrome” – (obesity,
hypertension, dyslipidemia, insulin resistance)

Dept. of Pharmacology, GMC 62

Amritsar
 Adverse effects
• Oedema
• Weight gain
• Decreased hematocrit and hemoglobin
• Elevated liver enzyme activity

Dept. of Pharmacology, GMC 63

Amritsar

Meglitinides
• Repaglinide and Nateglinide
• Non-sulfonylurea insulin secretagogues
characterized by a very rapid onset and short
duration of action.
• Directly stimulate first-phase insulin secretion in
the pancreatic beta cells
• Rapid release of insulin and quick onset of
action, total duration is short.
• No weight gain
• No hypoglycaemia
Dept. of Pharmacology, GMC 64
Amritsar
 Common adverse events
• Hypoglycemia
• Upper respiratory tract infection
• Rhinitis
• Bronchitis
• Headache

Dept. of Pharmacology, GMC 65

Amritsar

α-Glucosidase Inhibitors
• Acarbose and Miglitol
• Oral anti-hyperglycemic compounds
• Block the enzymatic degradation of complex
carbohydrates in the small intestine and slows
their absorption.
• Competitive, reversible inhibitors of pancreatic
α-amylase and membrane-bound intestinal α-
glucosidase hydrolase enzymes present in the
brush border of the intestine.
• Used as adjunctive therapy
Dept. of Pharmacology, GMC 66
Amritsar
 Other agents
• Herbals
– Mormordica charantia bitter gourd
– Trigonella foenum-graecum – fenugreek
• Nutraceuticals
– Antioxidants and vitamins
• Alpha lipoic acid, vit. E, Niacin, L-arginine, COq10
– Minerals and trace elements
• Chromium, vanadium, magnesium
– Polyunsaturated fatty acids

Dept. of Pharmacology, GMC 67

Amritsar

Options for Monotherapy

• Sulphonylureas
– Recently diagnosed type 2 DM or < 5 years
– Advantages
• Rapid FBG reduction
• Low cost
• Minimal adverse effects
– Diadvantages
• Risk of hypoglycaemia
• Weight gain
• No reduction of CV Risk

Dept. of Pharmacology, GMC 68

Amritsar
 Meglitinides
• Recently diagnosed type 2 DM
• Elevated PPG
• Advantages
– Decreased risk of hypoglycaemia
– Short acting
– Meal adjusted dosing
• Disadvantage
– High cost
Dept. of Pharmacology, GMC 69
Amritsar

Biguanides
• Obese type 2 DM
• Insulin resistant
• Advantages
– No weight gain
– Decreased risk of hypoglycaemia
– Can be combined with other OHAs for added
benefit
• Disadvantages
– GI side effects
– Risk of lactic acidosis
Dept. of Pharmacology, GMC 70
Amritsar
 Thiazolidinediones
• Insulin resistant
• Overweight
• Advantages
– Decreased risk of hypoglycaemia
– Decreased circulating insulin
• Disadvantages
– High cost
– Weight gain
– Liver toxicity?
– Slow onset of action

Dept. of Pharmacology, GMC 71

Amritsar

Combination Therapy
• Sulphonylurea + Biguanide OR
Thiazolidinediones OR α-glucosidase
inhibitor
• Biguanide + meglitinide
• Biguanide + thiazolidinedione
• Sulphonylurea + Biguanide +
thiazolidinedione (OR α-glucosidase
inhibitor)
• Insulin + Oral agent
Dept. of Pharmacology, GMC 72
Amritsar