08-07-2025

Insulin,
Oral Antidiabetic Drugs and
Glucagon

Diabetes mellitus (DM)

• Metabolic disorder
• Characterized by
• Hyperglycaemia
• Fasting plasma glucose ≥126 mg/dl
• ≥ 200 mg/dl 2 hours after 75 g oral glucose,
• Glycosuria
• Hyperlipidaemia
• Negative nitrogen balance
• Sometimes ketonaemia

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Definition and Classification

• Diabetes is a chronic condition caused by an

absolute lack of insulin or relative lack of insulin as
a result of impaired insulin secretion and action.

• Hallmark:
 Symptomatic glucose intolerance resulting in
hyperglycemia
 Alterations in lipid and protein metabolism.
• Genetically, etiologically, and clinically, diabetes is a
heterogeneous group of disorders.

Pathological changes:

• Thickening of capillary basement membrane

• Increase in vessel wall matrix and cellular proliferation
resulting in vascular complications like
 Lumen narrowing
 Early atherosclerosis
 Sclerosis of glomerular capillaries
 Retinopathy
 Neuropathy
 Peripheral vascular insufficiency.

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Glycated Hemoglobin?

• Enhanced nonenzymatic glycosylation of tissue proteins

• Persistent exposure to high glucose concentrations

• Accumulation of larger quantities of sorbitol (a reduced

product of glucose) in tissues

The concentration of glycosylated haemoglobin (HbA1c)

is taken as an index of protein glycosylation: it reflects the
state of glycaemia over the preceding 2–3 months.

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Other Rare Forms of DM

• Those due to specific genetic defects (type-3)

like ‘maturity onset diabetes of young’ (MODY)
• Other endocrine disorders
• Pancreatectomy
• ‘Gestational diabetes mellitus’ (GDM, type-4).

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Insulin

• Discovered in 1921 by Banting and Best

• First obtained in pure crystalline form in 1926

• The chemical structure was fully worked out in 1956

by Sanger.

Structure

• Two chain polypeptide having 51 amino acids and

MW about 6000.
• A-chain has 21 AA
• B-chain has 30 AA

The A and B chains are held together by two disulfide bonds.

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Insulin is synthesized in the β cells of pancreatic islets

Single chain peptide Pre-proinsulin (110 AA)

from which 24 AAs are first removed to produce

Proinsulin (86 AA)

The connecting or ‘C’ peptide (35 AA) is split off by

proteolysis in Golgi apparatus.

Both insulin and C peptide are stored in granules

within the cell.

The C peptide is secreted in the blood along with insulin

STRUCTURE OF INSULIN

Pro-Insulin 35 Amino Acids

Chain A: 21 Amino Acids

Chain B: 30 Amino Acids

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Insulin

Regulation of insulin secretion

• Under basal condition ~1U insulin is secreted per hour by

human pancreas.

• Much larger quantity is secreted after every meal.

• Secretion of insulin from β cells is regulated by:

 Chemical
 Hormonal
 Neural mechanisms

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1. Chemical Regulation

The β cells have a glucose sensing mechanism.

Entry of glucose into the β cells (through glucose transporter GLUT1)

Phosphorylation of Glucose by glucokinase

Glucose metabolism leads to activation of the glucosensor

Production of ATP, it inhibits the ATP-sensitive K+ channel (K+ ATP)

Partial depolarization of the β cells

Increase in intracellular Ca2+

(due to increased influx, decreased efflux and release from
intracellular stores)

Exocytotic release of insulin storing granules

Other nutrients evoking insulin release—amino

acids, fatty acids and ketone bodies, but glucose is
the principal regulator.

Glucose induces a brief pulse of insulin output

within 2 min (first phase) followed by a delayed
but more sustained second phase of insulin
release.

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• Glucose and other nutrients are 2–4 times more effective in

invoking insulin release when given orally than i.v.

• They generate chemical signals ‘incretins’ from the gut which

act on β cells in the pancreas to cause anticipatory release of
insulin.

• The incretins involved are

• Glucagon-like peptide-1 (GLP-1)
• Glucose-dependent insulinotropic polypeptide (GIP),
• Vasoactive intestinal peptide (VIP),
• Pancreozymin- cholecystokinin, etc.

• Various incretins may mediate signal from different nutrients.

• Glucagon and some of these peptides enhance insulin release by

increasing cAMP formation in the β cells

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2. Hormonal Regulation

Many hormones, e.g.

Growth hormone,
Corticosteroids,
Thyroxine
modify insulin release in response to glucose.

Types of cells in pancreas

β cells:
Constitute the core of the islets
Most abundant cell type
Secrete insulin
α cells:
Comprising 25% of the islet cell mass
Surround the core
Secrete glucagon
δ cells:
Comprising 5–10%
Interspersed between the α cells
Secrete somatostatin

F Cells: There are some PP (pancreatic polypeptide containing)

cells as well. Digestion of food by inhibiting gastric emptying.

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These hormones influence each other’s secretion:

• Somatostatin inhibits release of both insulin and glucagon.

• Glucagon provokes release of insulin as well as somatostatin.

• Insulin inhibits glucagon secretion. Amylin, another β cell

polypeptide released with insulin, inhibits glucagon secretion
through a central site of action in the brain.

3. Neural regulation

The islets are richly supplied by sympathetic and vagal

nerves.

• Adrenergic α2 receptor activation decreases insulin release

(predominant) by inhibiting β cell adenylyl cyclase.

• Adrenergic β2 stimulation increases insulin release (less

prominent) by stimulating β cell adenylyl cyclase.

• Cholinergic—muscarinic activation by Ach or vagal

stimulation causes insulin secretion through IP3/DAG-
increased intracellular Ca2+ in the β cells.

However, neural influences have only modulatory effect on

insulin secretion

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ACTIONS OF INSULIN

• The overall effects of insulin are to

 dispose meal derived glucose,
 amino acids,
 fatty acids and
 favour storage of fuel.

• It is a major anabolic hormone:

 promotes synthesis of gylcogen, lipids and protein.

1. Insulin facilitates glucose transport across cell membrane:

• Skeletal muscle and fat are highly sensitive. The availability

of glucose intracellularly is the limiting factor for its
utilization.

• Muscular activity induces glucose entry in muscle cells

without the need for insulin. As such, exercise has insulin
sparing effect

• Glucose entry in liver, brain, RBC, WBC and renal

medullary cells is largely independent of insulin.

• Ketoacidosis interferes with glucose utilization by brain and

contributes to diabetic coma.

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2. Intracellular utilization of glucose

• The first step in intracellular utilization of glucose:

glucose

phosphorylation

glucose- 6-phosphate

This is enhanced by insulin through increased production of

glucokinase.

Liver, muscle and fat

Insulin facilitates this by stimulating
the enzyme glycogen synthase

Glycogen synthesis (Glycogenesis)

Glycogen in Liver
Insulin inhibits glycogen degrading
enzyme phosphorylase

Degrades in Glucose (glycogenolysis)

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3. Insulin inhibits gluconeogenesis

Protein, FFA and Glycerol in Liver

Phosphoenol pyruvate carboxykinase

Glucose (Gluconeogenesis)
Insulin decreases
gene mediated
synthesis

In insulin deficiency → proteins and amino acids go from

peripheral tissues to liver → converted to carbohydrate and urea

Thus, in diabetes there is underutilization and over production

of glucose leading to hyperglycaemia and glycosuria.

4. Insulin inhibits lipolysis

Insulin inhibits lipolysis in adipose tissue and favours

triglyceride synthesis.

In diabetes increased amount of fat is broken down due to

unchecked action of lipolytic hormones (glucagon, Adr,
thyroxine, etc.)

Increased FFA and glycerol in blood

Taken up by liver to produce acetyl-CoA

Normally acetyl-CoA is resynthesized

to fatty acids and triglycerides, but
this process is reduced in diabetics

Acetyl CoA is diverted to produce ketone bodies

(acetone, acetoacetate, β-hydroxy-butyrate)

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The ketone bodies are released in blood and partly used up

by muscle and heart as energy source,
but
when their capacity is exceeded, ketonaemia and ketonuria
result.

QUIZ

What is the difference between Ketonaemia and Ketonuria?

Ketonemia is the elevated concentration of ketone bodies in

the blood

Ketonuria refers to the presence of ketone bodies in the urine

5. Insulin enhances transcription of vascular endothelial

lipoprotein lipase, thereby accelerating clearance of VLDL and
chylomicrons.
Normal Condition

6. Insulin facilitates AA entry into muscles and most other cells

Protein synthesis is enhanced,

and protein breakdown is inhibited
Insulin Deficiency

Protein breakdown
→ AAs are released in blood → taken up by
liver and converted to pyruvate, glucose and urea

The excess urea produced is excreted in urine resulting in

negative nitrogen balance.

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TIMELINE OF INSULIN ACTIVITY

Rapid Actions:

• Most of the previously mentioned metabolic actions of

insulin are exerted within seconds or minutes and are called
rapid actions

Intermediate actions:

• Others involving DNA mediated synthesis of glucose

transporter and some enzymes of amino acid metabolism
have a latency of few hours—the intermediate actions.

Long Term Effects

• In addition insulin exerts major long-term effects on

multiplication and differentiation of many types of cells.

MECHANISM OF ACTION OF INSULIN

• Insulin acts on specific receptors located on the cell membrane

of practically every cell
but
their density depends on the cell type: liver and fat cells are very
rich

• The insulin receptor is a receptor tyrosine kinase (RTK)

which is:
 Hetero-tetrameric glycoprotein
 Consisting of 2 extracellular α and 2 transmembrane β
subunits linked together by disulfide bonds.
 It is oriented across the cell membrane as a heterodimer

• The α subunits carry insulin binding sites, while the β subunits

have tyrosine protein kinase activity.

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Outside Cell

Di-sulfide bond

Cell Membrane

Inside Cell

INSULIN RECEPTOR

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Fig. : A model of insulin receptor and mediation of its

metabolic and cellular actions

T—Tyrosine residue;
GLUT4—Insulin dependent glucose transporter
IRS—Insulin receptor substrate proteins
PIP3—Phosphatidyl inositol trisphosphate
PI3 kinase—Phosphatidylinositol-3 kinase
GNE proteins—Guanine nucleotide exchange
proteins
MAP kinase—Mitogen-activated protein kinase
T-PrK—Tyrosine protein kinase
Ras—Regulator of cell division and differentiation
(protooncogene product)

FATE OF INSULIN

• Insulin is distributed only extracellularly.

• It is a peptide, and gets degraded in the g.i.t. if given orally.

• The plasma t½ of insulin is 5–9 min.

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PREPARATIONS OF INSULIN

Older commercial insulin preparations

• Beef pancreas
• Pork pancreas

Those were antigenic

• Contained ~1% (10,000 ppm) of other proteins
(proinsulin, other polypeptides, pancreatic proteins,
insulin derivatives, etc.).

Such insulins are no longer produced

Current insulin preparations:

• Purified pork/beef insulins
• Recombinant human insulins
• Insulin analogues

Highly purified insulin preparations

• Mono-component Insulin: In the 1970s improved

purification techniques like gel filtration and ion-
exchange chromatography were applied to
produce ‘single peak’ and ‘monocomponent
(MC)’ insulins

• Contain <10 ppm proinsulin.

• The MC insulins are more stable and cause less

insulin resistance or injection site lipodystrophy.

• The immunogenicity of pork MC insulin is

similar to that of recombinant human insulin.

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TYPES OF INSULIN PREPARATIONS

Regular (soluble) insulin

• Buffered neutral pH solution of unmodified insulin stabilized

by a small amount of zinc.

• At the concentration of the injectable solution, the insulin

molecules self aggregate to form hexamers around the zinc
ions.

• After s.c. injection, insulin monomers are released gradually

by dilution, so that absorption occurs slowly.

• Regular insulin is optimally injected s.c, 1 hour before a

meal.

• Does not provide low constant basal level

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Lente insulin (Insulin-zinc suspension)

Two types of insulin-zinc suspensions

• Ultra lente: The one with large particles is

crystalline and practically insoluble in water- long-
acting.
• Semi Lente: The other has smaller particles and is
amorphous- short-acting.

Their 7:3 ratio mixture is called ‘Lente insulin’ and is

intermediate-acting.

Isophane (Neutral Protamine Hagedorn or NPH) insulin:

• Protamine is added in a quantity just sufficient to complex all

insulin molecules.

• Neither insulin nor protamine is present in free form and pH

is neutral.

• On s.c. injection, the complex dissociates slowly to yield an

intermediate duration of action.

• It is mostly combined with regular insulin (70:30 or 50:50)

and injected s.c. twice daily before breakfast and before
dinner (split-mixed regimen).

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Human insulins

In the 1980s, the human insulins were produced by recombinant

DNA technology.

Having the same amino acid sequence as human insulin.

They were produced in/by

• Escherichia coli—‘proinsulin recombinant bacterial’ (prb)

• Yeast—‘precursor yeast recombinant’ (pyr),

• ‘Enzymatic modification of porcine insulin’ (emp)

Human insulin is also modified similarly to produce isophane

(NPH) and lente preparations.

Insulin analogues

• Analogues of insulin, greater stability and consistency

• Produced using recombinant DNA technology

• Have modified pharmacokinetics on s.c. injection

• Similar pharmacodynamic effects and immunogenicity

• Types:
 Insulin Lispro
 Insulin Aspart
 nsulin Glulisine
 Insulin Glargine
 Insulin Detemir
 Insulin Degludec

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REACTIONS TO INSULIN

Hypoglycaemia

• Most frequent and potentially the most serious

• More common in patients of ‘labile’ diabetes in whom insulin

requirement fluctuates unpredictably

• Hypoglycaemia can occur in any diabetic:

• Following inadvertent injection of large dose
• By missing a meal after injection
• By performing vigorous exercise

• Symptoms due to counter-regulatory sympathetic stimulation:

sweating, anxiety, palpitation, tremor

• Symptoms due to deprivation of the brain of its essential

nutrient glucose (neuroglucopenic symptoms)— dizziness,
headache, behavioural changes, visual disturbances, hunger,
fatigue, weakness, muscular

• Incoordination and sometimes fall in BP.

• Hypoglycaemic unawareness (loss of warning symptoms)

tends to develop in patients who experience frequent episodes
of hypoglycaemia.

• Finally, when blood glucose falls further (to < 40 mg/dl)

mental confusion, abnormal behaviour, seizures and coma
occur.

• Irreversible neurological deficits are the sequelae of

prolonged hypoglycaemia.

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Treatment: Glucose (or glucose yielding carbohydrate, e.g.

sugar) 15–20 g orally reverses the symptoms rapidly in most
cases

Local reactions

• Swelling, erythema and stinging sometimes occur at the

injected site, especially in the beginning.

• Lipodystrophy of the subcutaneous fat around the injection

site occurred occasionally with the older pork/beef insulin
preparations.

• This is rare with the newer preparations.

Allergy

• This is due to contaminating proteins, and is very rare

with human/highly purified insulins.

• Urticaria, angioedema and anaphylaxis are the

manifestations.

Edema

• Some patients develop short-lived dependent edema

(due to Na+ retention) when insulin therapy is
started.

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DRUG INTERACTIONS

1. β adrenergic blockers:
• Prolong hypoglycaemia by inhibiting compensatory
mechanisms operating through β2 receptors (β1
selective blockers are less liable).
• Warning signs of hypoglycaemia like palpitation,
tremor and anxiety are masked.

2. Thiazides, furosemide, corticosteroids, oral contraceptives,

salbutamol, nifedipine tend to raise blood sugar and reduce
effectiveness of insulin.

3. Acute ingestion of alcohol can precipitate hypoglycaemia

by depleting hepatic glycogen.

4. Lithium, high dose aspirin and theophylline may also

accentuate hypoglycaemia by enhancing insulin secretion,
as well as peripheral glucose utilization.

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USES OF INSULIN

Diabetes mellitus

Insulin is needed by such patients when:

• Not controlled by diet and exercise or when these are not

practicable.

• Primary or secondary failure of oral antidiabetics or when

these drugs are not tolerated.

• Temporarily to tide over infections, trauma, surgery,

pregnancy. In the perioperative period and during labour,
monitored i.v. insulin infusion is preferable.

• Any complication of diabetes, e.g. ketoacidosis, nonketotic

hyperosmolar coma, gangrene of extremities.

• Most type 1 patients require 0.4–0.8 U/kg/day.

• In type 2 patients, insulin dose varies (0.2–1.6 U/kg/day) with

the severity of diabetes and body weight

• Obese patients require higher per kg doses due to relative

insulin resistance.

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Diabetic ketoacidosis (Diabetic coma)

• Ketoacidosis of different grades generally occurs in insulin

dependent diabetics.

• It is infrequent in type 2 DM.

• The most common precipitating cause is infection.

• Others are:
• trauma, stroke, pancreatitis, stressful conditions
• inadequate doses of insulin.

• Typically they are dehydrated, hyperventilating and have impaired

consciousness.

• Close monitoring of vital signs, plasma glucose, blood pH,

electrolytes, plasma acetone, etc. is needed.

Management of Diabetic ketoacidosis

1. Insulin

• Regular insulin is used to rapidly correct the metabolic

abnormalities.

• A bolus dose of 0.1–0.2 U/kg i.v. is followed by 0.1 U/kg/hr

infusion; the rate is doubled if no significant fall in blood
glucose occurs in 2 hr.

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2. Intravenous fluids

• Correction of dehydration is vital.

• Normal saline is infused i.v., initially at the rate of 1 L/hr,

reducing progressively to 0.5 L/4 hours depending on the
volume status.

3. KCl

• Though upto 300 mEq of K+ may be lost in urine during

ketoacidosis, serum K+ is usually normal due to exchange
with intracellular stores.

4. Sodium bicarbonate

• It is not routinely needed. Acidosis subsides as ketosis is

controlled.

5. Phosphate

• When serum PO4 is in the low-normal range, 3–4 m mol/hr of

pot. phosphate infusion is advocated.

• Faster phosphate infusion can precipitate tetany, and its routine

use is not required.

6. Antibiotics and other supportive measures as well as treatment of

precipitating cause must be instituted simultaneously.

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Newer insulin delivery devices

1. Insulin syringes
2. Pen devices
3. Inhaled insulin
4. Insulin pumps
5. Implantable pumps

ORAL ANTIDIABETIC DRUGS

• The early sulfonamides tested in 1940s produced
hypoglycaemia as side effect. Taking this lead, the first
clinically acceptable sulfonylurea tolbutamide was introduced
in 1957.

• Others followed soon after. In the 1970s many so called

‘second generation’ sulfonylureas were developed which are
>100 times more potent than tolbutamide.

• Clinically useful biguanide phenformin was produced parallel

to sulfonylureas in 1957.

• Newer approaches have constantly been explored and have

successively yielded thiazolidinediones, meglitinide analogues,
α-glucosidase inhibitors, DPP-4 inhibitors and sod-glucose
cotransport (SGLT-2) inhibitors, etc.

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CLASSIFICATION OF ORAL ANTIDIABETIC DRUGS

GLP-1 Agonists: Exenatide

Liraglutide
Amylin Analogues: Pramlintide

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR

AGONISTS

• GLP-1 receptors are cell surface GPCRs expressed on:

 β and α cells
 Central and peripheral neurons
 Gastrointestinal mucosa, etc.

• GLP-1: incretin released from the gut in response to ingested

glucose

• GLP-1 Functioning:
 Induces insulin release from pancreatic β cells,
 Inhibits glucagon release from α cells
 Slows gastric emptying
 Suppresses appetite by activating specific GLP-1
receptors

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• GLP-1 based therapy appears to be the most effective

measure to preserve β cell function in type 2 DM.

• GLP-1 itself is not suitable for clinical use because of rapid

degradation by the enzyme dipeptidyl peptidase-4 (DPP-4)

• DPP-4 is expressed on the luminal membrane of capillary

endothelial cells, kidney, liver, gut mucosa and immune
cells.

• Some metabolically stable analogues of GLP-1 have been

produced for clinical use in type-2 DM.

• May cause hypoglycemia

Exenatide

• Synthetic GLP-1 receptor agonist.

• DPP-4 resistant
• Being a peptide, it is inactive orally., Given s.c.
• Given in combination with metformin/SU/pioglitazone in poorly
controlled type 2 diabetics.

Liraglutide

• This recently developed longer-acting GLP-1

• Agonist, given s.c

Albiglutide and dulaglutide

• Very long acting GLP-1 receptor agonists

• Need to be injected once weekly.
• Given s.c

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Mode of Action of GLP-1 Analogues

AMYLIN ANALOGUE

• Also called ‘islet amyloid polypeptide’ (IAP)

• Produced by pancreatic β cells and is stored in the same

granules as insulin.

• Secreted along with insulin

• Acts in the brain to:

 Reduce glucagon secretion from α cells
 Delay gastric emptying,
 Retard glucose absorption
 Promote satiety

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Pramlintide

• Synthetic amylin analogue

• Given s.c. injection before meal

• Used to supplement meal time insulin injection when

insulin alone fails to control post prandial glycaemic
peak

SULFONYLUREAS

• K+-ATP Channel blockers

• Lowering of blood glucose level in normal subjects and in type 2

diabetics

• Only second generation SUs are employed now

• All first generation compounds have been discontinued except

tolbutamide which is infrequently used.

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Mechanism of action

• Bind to a specific ‘sulfonylurea receptor’ (SUR1) located

on the pancreatic β cell membrane and provoke a brisk
release of insulin.

• The SUs primarily augment the 2nd phase insulin secretion

with little effect on the 1st phase.

• Do not cause hypoglycaemia.

Mechanism of Action

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Adverse effects

Incidence of adverse effects is quite low (3–7%).

Hypoglycaemia

Nonspecific side effects

• Weight gain 1–3 kg weight.
• Nausea, vomiting, flatulence, diarrhoea or constipation,
headache and paresthesias are generally mild and infrequent.

3. Hypersensitivity
• Rashes, photosensitivity, purpura, transient leukopenia, rarely
agranulocytosis.
• Flushing and a disulfiram-like reaction after alcohol is reported
to occur in some individuals taking SUs.

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MEGLITINIDE/D-PHENYLALANINE ANALOGUES
(K+-ATP Channel blockers)

Though not a sulfonylurea, acts in an analogous manner by

binding to SUR → closure of ATP sensitive K+ channels →
depolarisation → insulin release

Repaglinide

• It is meglitinide analogue

• Indicated only in selected type 2 diabetics who suffer

pronounced postprandial hyperglycaemia or to supplement
metformin/long-acting insulin.

• It should be avoided in liver disease.

Nateglinide It is a D-phenylalanine derivative

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

• Their blood sugar lowering efficacy is moderate compared to

that of SUs.

• DPP-4 inhibitors have emerged as important adjunctive drugs in

type 2 DM

Sitagliptin

• Competitive and selective DPP-4 inhibitor, potentiates the

action of GLP-1

• GLP, boosts postprandial insulin release, decreases glucagon

secretion and lowers meal-time as well as fasting blood glucose
in type 2 diabetics.

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• Sitagliptin monotherapy is recommended only when

metformin cannot be used.

• Most professional guidelines recommend DPP-4 inhibitors

primarily as adjuvant drugs in type 2 diabetics not well
controlled by metformin/SUs/pioglitazone or insulin.

Vildagliptin

• This DPP-4 inhibitor binds to the enzyme covalently.

• Longer duration of action

• Less selective than sitagliptin for DPP-4; causes some

inhibition of DPP-8, DPP-9 as well.

Saxagliptin

• Like vildagliptin, saxagliptin binds covalently with DPP-4

• Acts for 24 hours

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Teneligliptin

• It is a new DPP-4 inhibitor developed in Japan

• Exerts long-lasting (>24 hours) DPP-4 inhibition and

antiglycaemic effect.

• Following a single morning dose, postprandial

hyperglycaemia is suppressed at all 3 meals of the day.

• Therapeutic efficacy both as monotherapy as well as in

combination with metformin ± SUs or a thiazolidinedione
is comparable to other gliptins.

Mechanism of Action

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BIGUANIDE (AMPK ACTIVATOR)

• Two biguanide antidiabetics, phenformin and metformin were

introduced in the 1950s.

• Phenformin has been banned in India since 2003: Because of

higher risk of lactic acidosis.

Metformin

• It differs markedly from SUs: causes little or no hypoglycaemia

in nondiabetic subjects, and even in diabetics, hypoglycaemia is
rare.

• Hence, it is ‘euglycaemic’, rather than hypoglycaemic’.

• Improves lipid profile in type 2 diabetics.

Mechanism of action

• Biguanides do not cause insulin release.

• Presence of insulin is essential for their action.

• Activation of AMP-dependent protein kinase (AMPK) to play a

crucial role in mediating the actions of metformin, the key
features of which are:

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1. Major action : Suppresses hepatic gluconeogenesis and glucose

output from liver.

2. Enhances insulin-mediated glucose uptake and disposal in skeletal

muscle and fat.
This translates into
–– glycogen storage in skeletal muscle
–– reduced lipogenesis in adipose tissue and
–– enhanced fatty acid oxidation.

3. Interferes with mitochondrial respiratory chain and promotes

peripheral glucose utilization through anaerobic glycolysis.

AMPK activation by metformin appears to be an indirect

consequence of interference with cellular respiration and lowering of
intracellular ATP and other energy sources.

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Adverse Effects of Metformin

• Lactic acidosis
• Vit B12 deficiency
• Metformin is contraindicated in renal insufficiency, because
risk of lactic acidosis increases.
• It should also not be given in hypotensive states, heart
failure, severe respiratory/hepatic disease, as well as in
alcoholics.

Uses of Metformin

Metformin is now established as a first choice drug for all

type 2 DM patients, except when not tolerated or
contraindicated.

Advantages of metformin are:

• Antihyperglycaemic, but not hypoglycaemic

• Weight loss promoting

• Has potential to prevent macrovascular as well as

microvascular complications of diabetes

• No acceleration of β cell exhaustion/ failure in type 2 DM.

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• Infertility: Metformin has been found to improve ovulation

and fertility in some infertile women with polycystic ovary.
This benefit is observed irrespective of the glycaemic status
of the woman; may be due to mitigation of insulin
resistance and lowering of circulating insulin levels

Thiazolidinedione (PPARγ AGONIST)

• Also known as “insulin sensitizers”

• Rosiglitazone is banned in India since 2010 and has been

withdrawn in Europe due to unacceptable increase in risk of
myocardial infarction, CHF, stroke and death.

• Only one thiazolidinedione Pioglitazone is currently available

in India.

• Because of some reports linking pioglitazone with carcinoma

of urinary bladder, it was banned in India in June 2013.

• However, within 2 months the ban was lifted with a warning

label ‘not to use it as a first line drug’.

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Mechanism of action

• PPARγ is a transcription factor, a member of a superfamily of

nuclear receptors including thyroid and steroid receptors.

• These drugs are synthetic ligands for the transcription factor

PPARγ

• PPARγ is expressed in multiple tissue types (e.g. skeletal

muscle, fat and liver).

• PPARγ stimulation upregulates the expression of genes involved

in lipid and glucose metabolism, insulin signal transduction, and
adipocyte differentiation.

• As illustrated, one mechanism contributing to the hypoglycemic

effect of thiazolidinediones is an increased expression of the
glucose transporter GLUT4.

• The increased expression of GLUT4 (in addition to

mediators of insulin signal transduction) increases the
ability of cells (e.g. adipocytes) to take up glucose when
stimulated by insulin.

• Pioglitazone, in addition, lowers serum triglyceride level

and raises HDL level without much change in LDL level,
probably because it acts on PPARα as well to induce
expression of reverse cholesterol transporter and some
apoproteins.

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α GLUCOSIDASE INHIBITORS

Acarbose

• It is a complex oligosaccharide which reversibly inhibits

α-glucosidases, the final enzymes for the digestion of
carbohydrates in the brush border of small intestine
mucosa.

• It slows down and decreases digestion and absorption of

polysaccharides (starch, etc.) and sucrose. In addition,
GLP-1 release is promoted which may contribute to the
effect.

• Acarbose is a mild antihyperglycaemic and not a

hypoglycaemic; may be used as an adjuvant to diet (with
or without metformin/SU) in obese diabetics.

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Acarbose

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DOPAMINE D2 AGONIST

Bromocriptine

• Recently (2009) a quick release oral formulation of

bromocriptine has been approved by US-FDA for
adjunctive treatment of type 2 DM.

• Taken early in the morning it is thought to act on the

hypothalamic dopaminergic control of the circadian
rhythm of hormone (GH, prolactin, ACTH, etc.) release
and reset it to reduce insulin resistance.

• Bromocriptine can be taken alone to supplement

diet+exercise or added to metformin or SU or both.

SODIUM-GLUCOSE CO-TRANSPORT-2 (SGLT-2)

INHIBITOR

• Practically all the glucose filtered at the glomerulus is

reabsorbed in the proximal tubules.

• The major transporter which accomplishes this is SGLT-2,

whose inhibition induces glucosuria and lowers blood
glucose in type 2 DM, as well as causes weight loss.

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GLUCAGON

• A hyperglycaemic principle was demonstrated to be present

in the pancreatic islets just two years after the discovery of
insulin in 1921. It was named ‘glucagon’.

• Glucagon is a single chain polypeptide containing 29

amino acids, MW 3500.

• It is secreted by the α cells of the islets of Langerhans

• Commercially produced now by recombinant DNA

technology.

Regulation of Secretion

• Like insulin, glucagon is also derived by cleavage of a

larger peptide prohormone.

• Its secretion is regulated by glucose levels, other

nutrients, paracrine hormones and nervous system.

• Glucose has opposite effects on insulin and glucagon

release, i.e. high glucose level inhibits glucagon secretion.

• The incretin GLP-1, FFA and ketone bodies also inhibit

glucagon release.

• Amino acids, however, induce both insulin and glucagon

secretion.

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• Insulin, amylin and somatostatin, elaborated by the

neighboring β and δ cells, inhibit glucagon secretion.

• Sympathetic stimulation consistently and parasympathetic

stimulation under certain conditions evokes glucagon
release.

Actions

• Glucagon is hyperglycaemic; most of its actions are

opposite to that of insulin.

• Glucagon causes hyperglycaemia primarily by enhancing

glycogenolysis and gluconeogenesis in liver.

• It plays an essential role in the development of diabetic

ketoacidosis.

• Increased secretion of glucagon has been shown to attend all

forms of severe tissue injury.

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Mechanism of action

Glucagon, through its own receptor

and coupling Gs protein activates
adenylyl cyclase and increases
cAMP in liver, fat cells, heart and
other tissues; most of its actions are
mediated through this cyclic
nucleotide.

Uses

1. Hypoglycaemia

• Use of glucagon to counteract insulin/ oral hypoglycaemic

drug induced hypoglycaemia is only an expedient
measure for the emergency, and must be followed by oral
glucose/sugar given repeatedly till the blood glucose level
stabilizes.
• It may not work if hepatic glycogen is already depleted.
• Dose: 0.5–1.0 mg i.v. or i.m.
• GLUCAGON 1 mg inj.

2. Cardiogenic shock

• Glucagon may be used to stimulate the heart in β

adrenergic blocker treated patients. However, action is not
very marked.

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