2. Structure of insulin
Insulin is a protein comprising
of 2 polypeptide chains:
ā¢ chain A with 21 amino acid
residues
ā¢ chain B with 30 amino acid
residues
3. Structure of insulin
ā¢ Chains A and B are linked by
disulphide bridges.
ā¢ A-chain contains an intra-chain
disulphide bridge linking residue 6
and 11.
ā¢ C-chain connects A and B chains.
ā¢ C-chain is liberated along with
insulin after breakdown of
proinsulin.
4. Structure of insulin
Insulin monomers aggregate to
form dimers and hexamers.
Zn hexamer is composed of
three insulin dimmers associated
in threefold symmetrical pattern.
5.
6. Biosynthesis of insulin
Insulin is synthesized in the beta
cells of pancreas in the form of
preproinsulin.
Preproinsulin is the ultimate
precursor.
Gene for preproinsulin is located on
chromosome 11 close to that for
insulin like growth factor-2 (IGF-2).
7. Biosynthesis of insulin
ā¢ Within a minute after synthesis
preproinsulin is discharged into cisternal
space of rough endoplasmic reticulum.
ā¢ In the rER it is cleaved into proinsulin by
proteolytic enzymes.
ā¢ Proinsulin has a C (connecting chain)
linking A and B chains.
ā¢ Proinsulin is transported by microvesicles
to the Golgi apparatus.
8. Biosynthesis of insulin
ā¢ Proinsulin is released in vesicles.
ā¢ Conversion of proinsulin to insulin
continues in maturing granules
through the action of prohormone
convertase 2 and 3 and carboxy
peptidase H.
ā¢ Maturing granules are translocated
with the help of microtubules and
microfilaments.
9. Biosynthesis of insulin
Insulin
Preproinsulin
Removal of the signal
peptide: N signal
peptide
Proinsulin
Disulfide bridge
formation
Insulin
Insulin with A and B
chain and disulfide
bridges Proinsulin
Removal of
the C chain
10. Insulin secretion
ā¢ Insulin is secreted from the beta cells in
response to various stimuli like glucose,
arginine, sulphonylureas...
ā¢ Glucose is the major determinant.
ā¢ Glucose is taken up by beta cells through
GLUT-2 receptors.
ā¢ After entering the beta cell, glucose is
oxidized by glucokinase.
ā¢ Glucokinase acts as a glucose sensor.
11. Insulin secretion
ā¢ Glucose concentration below 90 mg/dL
does not cause any insulin release.
ā¢ At such substimulatory glucose
concentrations, K+ efflux through open
KATP channels keeps the Ī² cell membrane
at a negative potential at which voltage-
gated Ca2+ channels are closed.
ā¢ If there is increase in plasma glucose,
glucose uptake and metabolism by the Ī²
cell is enhanced.
12. Insulin secretion
Rise in ATP concentration results in
closure of KATP channels, leading to:
ā¢ membrane depolarization
ā¢ opening of voltage-gated Ca2+ channels
ā¢ Ca2+ influx
ā¢ rise in intracellular calcium
concentration
ā¢ exocytosis of insulin granules
13. KATP channels
The pancreatic KATP channel
consists of two unrelated subunits:
ā¢ sulfonylurea receptor (SUR1
isoform)
ā¢ potassium channel subunit
(Kir6.2) that forms the central
ion-conducting pathway
14. KATP channels
ā¢ The mature KATP channel exists as
an octamer of Kir6.2 and SUR1
subunits in a 4:4 stoichiometry.
ā¢ A subunit specific site specific to
pancreatic KATP channel, confers
glimepiride an advantage over the
other sulfonylurea secretagogues.
15. KATP channels
ā¢ Sulfonylurea and non-sulphonylurea
drugs act as insulin secretagogues by
closing KATP channels bypassing the Ī²
cell metabolism.
ā¢ Diazoxide is a K channel opener and
inhibits insulin secretion,
independent of blood glucose levels.
16. Literature
ā¢ Joshi SR, Parikh RM, Das AK.
Insulin-History, Biochemistry,
Physiology and
Pharmacology. Supplement
of JAPI. 2007;55:19-25.
ā¢ Biology.kenyon.edu