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INSULIN
ORAL HYPOGLYCEMIC AGENTS
GLUCAGON
PRESENTED
BY
SK ANJUM
Roll no :76

GLUCAGON
• Glucagon is a single-chain polypeptide of 21 amino acid residues synthesised
mainly in the A cell of the islets, but also in the upper gastrointestinal tract. It
has considerable structural homology with other gastrointestinal tract
hormones, including secretin, vasoactive intestinal peptide and GIP
• Decreased blood levels of glucose, sympathetic stimulation (as in exercise) and
high protein diet (rich in amino acids) stimulate glucagon release; while
hyperglycaemia and somatostatin inhibit glucagon secretion.
• If, however, the blood glucose-dependent negative feedback mechanism fails,
the A-cells will secrete glucagon continuously and hyperglycaemia would
result.

• Glucagon raises blood glucose levels by accelerating breakdown of glycogen
into glucose (glycogenolysis) and conversion of lactates and amino acids into
glucose in the liver (gluconeogenesis), releasing glucose into blood.
• GIT effects of glucagon include relaxation of the gut and inhibition of gastric
acid secretion. It has potent inotropic and chronotropic effects on heart. These
effects are similar to that produced by β1-adrenoceptor agonists without
involving the role of β1-receptors. It has a very short half life (3-5 min).

Therapeutic uses:
• Glucagon can be given intramuscularly or subcutaneously as well as intravenously.
• Treatment of hypoglycaemia in unconscious patients (who cannot drink), unlike
intravenous glucose, it can be administered by non-medical personnel.
• Treatment of acute cardiac failure precipitated by β-adrenoceptor antagonists.
Adverse effects :
• Adverse effects are rare but may include transient nausea and vomiting.

INSULIN
• Insulin is a 2 chain polypeptide having 51 amino acids and MW about 6000.
The A-chain has 21 AA while B- chain has 30 AA.
• Synthesized in the β cells of pancreatic islets as a single chain peptide
preproinsulin (110A) from which 24 amino acids are first removed to produce
Proinsulin.
• MOA : When blood glucose level increase β cells of islet of
Langerhans of pancreas release insulin.
• When blood glucose level decrease α cells of pancreas secrete
glucagon.

• Liver : convert glycogen into glucose and store in liver.
• Stimulate glucose uptake by cells cell ATP.
• Glucose uptake into tissue increases Blood glucose level decreases.
• Diabetes mellitus (DM) it is a metabolic disorder characterized by
hyperglycemia , glycosuria , hyperlipidemia , negative nitrogen balance and
sometimes ketonaemia.
 There are two types of DM TYPE 1 and TYPE II

DIABETES MELLITUS : TYPE 1
• Insulin-dependent diabetes mellitus (IDDM)/Juvenile onset diabetes
mellitus/ “childhood” diabetes.
• 10% of cases of DM, less common, low degree of genetic predisposition.
• Caused by inadequate production of insulin because T cell- mediated
autoimmune (type 1A) Response destroys beta cells (loss of pancreatic β
cells ).
• Circulating insulin levels are very low or very less.
• Decreased insulin , patients are more prone to ketosis.
• It Can be controlled by insulin injections.

TYPE II
• Non insulin dependent diabetes mellitus (NIDDM)/ maturity onset diabetes
mellitus .
• Adult diabetes : usually occurs after age 40 and in obese individuals due to
genetics, aging and peripheral insulin resistance.
• 90% case of diabetes mellitus has a higher degree of genetic predisposition.
• Insulin levels are normal or elevated but there is either a decrease in number
of insulin receptors or the cells cannot take it up (defective signal reception
in insulin pathway or reduced sensitivity of peripheral tissues to insulin)
• Controlled by dietary changes, regular exercise ,oral hypoglycemic agents.

TYPE III
• These types of diabetes occurs due to other cause like chronic therapy with
some drugs (thiazide urea, glucocorticoids , diazoxide , growth hormone) or
disease induced pancreatitis.
TYPE IV
• This is also called gestational diabetes.
• 4 to 5% of patients suffering from type IV diabetes
• Increased blood sugar level than normal generally occurs during third trimester
and after postpartum period.
• Placental hormone promotes insulin resistance.

RAPID EFFECTS
• Carbohydrate Metabolism
a) In Liver Cells: It decreases glycogenolysis by inhibiting glycogen
phosphorylase and increases glycogenesis by activating glycogen synthetase.
b) In Muscles: It facilitates glucose uptake by promoting translocation of the
intracellular glucose transporter-4 (GLUT-4) onto the cell surface. It promotes
glycogenesis (glycogen synthesis) and increases glycolysis.
c) In Adipose Tissues: It facilitates glucose uptake (through GLUT-4). It increases
intracellular glucose oxidative metabolism. Glycerol, thus produced, is
esterified with fatty acids to form triglycerides.

• Protein Metabolism
a) In Liver Cells: It decreases protein breakdown and inhibits oxidation of amino
acids to ketoacids.
b) In Muscles: It increases protein synthesis and increases amino acid uptake by
muscle cells to produce a net positive nitrogen balance.
• Fat Metabolism
a) In Liver Cells: It increases lipogenesis (i.e., conversion of glucose and other
nutrients to fatty acids)
b) In Adipose Tissues: It increases fatty acid synthesis and triglycerides formation
and storage', decreases lipolysis (hydrolysis or breakdown of fats) and blunts
lipolytic action of adrenaline, growth hormone and glucagon.

Oral Hypoglycemic AGENTS
 Oral Hypoglycemic Drugs:
• Sulfonyl urea Derivatives:
• First Generation: Tolbutamide , Chlorpropamide , Tolazomide , Acetohexamide .
• Second Generation: Glibenclamide , Glipizide , Gliclazide.
 Anti Hyperglycemic Drugs:
• Bioguanide : Phenformin, Metformin.
• Thiazolidine : Troglitazone, Coglitazone, Aeuglitazone, Pioglitazone.
• A- Glucosidase Inhibitors : Acarbose, Guargum, Miglitol.
 Parenteral Anti-diabetic Drugs: Insulin.

Sulfonyl Urea Derivatives:
Sulfonylurea:
• These are chemically related to sulfonamides but are deprived of antibacterial
activity. The examples of sulfonylureas are Tolbutamide, Tolzamide,
Chlorpropamide, Glibenclamide, Glipizide, Glyburide. These are readily absorbed
from the gastrointestinal tract, appear in the blood within 1-2 hrs and peak
levels are attained within 4-6 hrs. They are partially protein bound and
metabolized in liver

ADME:
o Sulfonylureas are well absorbed after oral administration. Glipizide absorption
is delayed by food. All sulfonylureas are highly protein bound (90- 98%).
Plasma protein binding is highest for glimepiride (98%). These are metabolised
in liver and/or kidney and excreted in urine. The duration of action for II
generation sulfonylureas is 24 hrs.
MOA :
o It blocks the ATP dependant K+ channel in the beta cell of the pancreas and
cause degranulation of beta cell to release insulin.
o Inhibits hepatic glycogenolysis.

Therapeutic uses:
o In type 2 diabetes mellitus.
o Surgery during diabetes.
o In diabetes coma.
ADR:
o Hypoglycemia,
o allergic skin reaction,
o bone marrow depression,
o cholestatic jaundice,
o Chlorpropamide may produce disulfiram like reaction.

Anti Hyperglycemic Drugs
Bioguanide:
Phenformin and metformin are two drugs which belong to the group biguanides. Out of
these, phenformin has been discontinued as it causes lactoacidosis and is devoid of any
long-term benefits. Metformin is the only drug in this class that is being currently used .
• MOA:
• They increase glucose uptake and utilization in skeletal muscle (thereby reducing insulin
resistance).
• Reduce hepatic and renal glucose gluconeogenesis, which reduced hepatic glucose
outputs.
• Slowing down the glucose absorption from GIT, which increases availability of glucose
for its conversion to lactate by entrecotes.
• It also promotes insulin binding to its receptor.

ADME :
• It has a plasma half life of 2-3 hrs and duration of action of about 6-10 . It is
not bound to plasma protein, not metabolised and is excreted unchanged by
the kidneys .
Clinical use :
• Metformin is the patient with type -2 diabetes . Instead of stimulating appetite it
causes anorexia and for this reason metformin is often used as first choice of
drug in treatment of obese type-2 diabetic cases .
• It can be combined with sulfonylureas , meglitinides and with glitazones to
treate insulin resistance syndrome .
• Metformin decrease the risk of macrovascular as well as microvascular disease .

Adverse effects :
• Adverse effects of metformin are nausea , metallic taste , anorexia , flatulence
and diarrhea.
• Long use may cause decrease absorption of vit B 12 .
• Alcohol ingestion can also precipitate severe lactic acidosis because alcohol
potentiates the effects of metformin on lactate metabolism

a-Glucosidase Inhibitors :
• Example of α-glucosidase inhibitor is acarbose and miglitol. It inhibits
intestinal α-glucosidase and inhibits the digestion and absorption of starch
and sucrose from the gut, therefore reduces post-prandial digestion and
absorption of carbohydrate and lower post meal hyperglycemia. Regular
use also tends to lower HbA1c, body weight and serum triglycerides.
ADVERSE EFFECTS :
• Flatulence, diarrhea and abdominal pain.

Thiazolidinediones (Glitazones)
• Examples are Rosiglitazone, Pioglitazone and Troglitazone are a newer class of
antihyperglycemic agents.
MOA:
• These are agonist of nuclear receptor called Peroxisome Proliferator-Activated
Receptor gamma (PPAR- γ ) ,The PPAR-γ receptor is expressed mainly in adipose
tissue but also in muscle and liver .
• . Activation of PPAR-γ receptor by glitazones increases lipogenesis and promote
uptake of fatty acid and glucose. It also reduce hepatic glucose output by
inhibiting hepatic gluconeogenesis, promote glucose uptake into muscle by
decreasing insulin resistance and decrease HbA1c level
Adverse effect:
• Weight gain, fluid retention, edema and hepatotoxicity

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