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1. INSULIN AND ITS
MECHANISM OF ACTION.
RAHUL SAH
(STRUCTURE OF INSULIN ) MBBS 1ST YEAR

2. LEARNING OBJECTIVES.
1. Introduction.
2. Biosynthesis.
3. Structure.
4. Mode of Insulin secretion.
5. Mechanism of action.
6. Functions.
7. Switch between carbohydrate and fat metabolism.
8. Regulation of Inulin.
9. Applied aspects.
10. References.

3. INTRODUCTION.
o Insulin is very powerful anabolic hormone.
o It was first isolated from the pancreas in 1922 by Banting and Best.
o Its level goes up when the body is rich in glucose, amino acids,
fatty acids, etc. i.e when there is abundance of nutrients.
o It increases the utilization and storage of nutrients. It also leads
to synthetic functions and cellular growth and differentiation
functions.

4. o Insulin is a protein synthesised and secreted by beta
cells of Islet of Langerhans of the pancreas .
Pre-pro-insulin (109 amino acids long).
Pro-insulin (86 amino acids long, converted in the
endoplasmic reticulum).
Active insulin (converted in the golgi apparatus).
BIOSYNTHESIS.

5. o Insulin is a protein with 2 polypeptide chains
i.e chain A and chain B.
o Chain A has 21 amino acids and chain B has 30
amino acids .
o They are joined together by 2 interchain
disulphide bonds, between A7 to B7 and A20
to B19.There is also an intrachain disulphide
chain between 6th and 11th amino acid of chain
A.
STRUCTURE OF INSULIN.

6. MECHANISM OF INSULIN
SECRETION.
Beta cells 60% Insulin, Amylin
Alpha cells 25% Glucagon
Delta cells 10% Somatostatin
PP cells 5% pancreatic polypeptides

7. MECHANISM OF INSULIN
SECRETION.
o Glucose enters into the beta cells through the GluT
2 transporter (insulin independent).
o Glucose is phosphorylated into Glucose-6-phosphate
by glucokinase.
o Glucose-6-phosohate undergoes oxidation to form
ATP.
o ATP causes closure of ATP sensitive potassium
channels found on the membrane of the beta cells .
o This leads to the depolarisation of the cell
membrane ,thereby opening voltage gated calcium
channels.
o Influx of calcium leads to docking of insulin
containing vesicles on the cell membrane .
o Thereby leading to the secretion of insulin into the
extracellular fluid.

8. o Insulin once secreted into the blood from the
beta cells, circulates almost entirely in unbound
form with plasma half life of about 6 minutes.
o Since insulin is a protein hormone, so because of
its large size and polar nature it cannot pass
through the cell membranes .
o So, it binds to a special membrane receptor
protein found on the cell membrane of target
cells.
MECHANISM OF ACTION.

9. Insulin binds to the alpha subunits.
Transformational change (alpha subunits).
Activation of enzyme Tyrosin kinase .
Cross-phosphorylation of Tyrosin residues of beta
subunits (autophosphorylation).
Phosphorylation of Insulin Receptor Substrate by
Tyrosin Kinase of beta subunits.
MECHANISM OF ACTION.

10. i) Activation of PI3K pathway
- Binding of GluT4 transporters to the cell
membrane.
- Influx of glucose
ii) activation of mTOR pathway
- Leads to lipid and protein synthesis and also
decreases lipolysis and proteolysis.
iii) activation of RAS-MAP-K pathway
- Helps in cell growth, differentiation and
proliferation.
NOTE: If insulin is not bound to the membrane
receptors of the target cells then it is degraded by
the enzyme Insulinase mainly in the liver.
MECHANISM OF ACTION.

11. FUNCTIONS.
– Effect on carbohydrate metabolism
1. Promotes muscle glucose uptake and
metabolism
2. Storage of glycogen in muscle
3. Promotes liver uptake, storage and usage
of glucose
4. Promotes glycogen synthesis
5. Promotes conversion of excess glucose into
fatty acids
6. Inhibits gluconeogenesis.
Effect on protein metabolism
1. Promotes protein synthesis and storage.
2. Prevents degradation of protein.

12. FUNCTIONS.
– Effect on fat metabolism
1. Insulin functions as fat sparer.
2. Inhibits action of enzyme lipase.
3. Promotes fat storage by promoting
formation of alpha glycerol phosphate.
– Effect on growth
Insulin & GH interact synergistically to
promote growth.

13. SWITCH BETWEEN CARBOHYDRATE AND FAT
METABOLISM.
1. Glucose conc low Insulin secretion supressed Fat is used as
source of energy everywhere (except brain) .
2. Glucose conc high Insulin secretion glucose used.
Counter-regulatory hormones that help in this switching.
1.Growth hormone
2.Cortisol
3.Epinephrine
4.Glucagon.

14. REGULATION OF INSULIN
SECRETION.
INCREASE DECREASE
1.Nutrients Blood glucose, fatty acids, amino
acids.
2.Hormones Growth hormone, glucagon,
cortisol, gastrointerstinal
hormones (gastrin,
cholecystokinin, etc).
Leptin, stomatostatin.
3.Neural control Parasympathetic stimulation. Sympathetic stimulation.
4.Drugs Sulphonylurea drugs (Glyburide,
Tolbutamide).
Metformin, Octreotide.

15. APPLIED ASPECTS.
1. DIABETES MELLITUS
- Syndrome of impaired carbohydrate, fat and protein metabolism.
-Types - Type 1 : Due to lack of insulin secretion.
Type 2 : Decreased sensitivity of target tissue to the metabolic effects of insulin
2. DIABETIC KETOACIDOSIS (DIABETIC COMA)
- Occurs due to lack of insulin.
- excess amounts of Ketone bodies are produced and left into the circulation.
3. INSULINOMA (HYPERINSULINISM)
- Excess amounts of insulin produced.
- Due to adenoma or adenocarcinoma of Islets of Langerhans.
- Leads to Insulin Shock.

16. REFERENCES.
BOOKS.
1. Textbook of Medical Physiology ,Gyton & Hall.
2. Textbook of BIOCHEMISTRY for Medical Students, DM Vasudevan.
SITES.
1. Dr Najeeb Lectures
2. ncbi.nlm.gov

17. THANK YOU.