Insulin

Insulin is a protein synthesized and secreted by the beta-cells of the islets of langerhans of the pancreas.

1. M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

2. PANCREAS
Both endocrine and exocrine
Endocrine function is localized in the islets of
Langerhans, epithelial cells that are dispersed
throughout the entire organ.
3 distinct types of cells namely
AlphaGlucagon
Beta  Insulin
Gama not known
Delta secretes & stores somatostatin

3. Insulin -- Introduction
Plays imp role in metabolism causing
Increased Carbohydrate Metabolism
Glycogen storage
Fatty acid synthesis
Amino acid uptake and
Protein synthesis
Thus imp anabolic hormone which acts on variety
of tissues including liver, fat and muscle.

4. chemistry
Protein hormone produced from the islets of Langerhans
which make up1% of the pancreas.
Crystallization requires Zn , which is a constituent of
stored insulin since normal islets are relatively rich in this
element.
Insulin is made up of 51 AAs arranged in 2 PP chains(A&B)
having a mol.wt of 5734.
2 inter chain and 1 intra chain –S-S- bonds
Insulin can not be administered orally
The pork pancreas is the most similar to human insulin.
The 2 insulins diff only in the terminal AA no of B
chain(30)
This terminal AA in porcine insulin is Ala and Thr in
Hum.

5. Chemistry
This terminal AA can be removed easily with CP.(retains
the biologic activity)
Thus it is possible to convert porcine insulin into a
Human ( 1 AA shorter)
Insulins from the pig, whale and dog are structurally
identical.
Those from the sheep, horse and cow differ form porcine
insulin only in 3 AAs under the –S-S brige in the A chain.
Other species may differ in as much as 29 out of the 51
AAs.
Two structurally diff insulins – isolated – a single rat
pancreas, diff by a single AA(Lys/Met) in the A chain.
The pancreas of certain fishes – more than one insulin

6. Structure of Insulin
Despite the wide variation in 1
0
structure , the bio. Activity
per unit wt is remarkably constant for all insulins.
It exists in Zn crystals as hexamers and dimers.
When diluted in the circulation, insulin exists as a
monomer.
The m-RNA for preproinsulin has been isolated from
islets, the complementary DNA synthesized and active
insulin has been sucessfully cloned in bacteria.
Therefore insulin is the first high mol.wt hormone to be
made by the process of molecular engineering.

7. Structure of Insulin
The 2
0
&3
0
structures of Bovine insulin have been
determined by X-ray crystallography.
These studies indicate that the A chain portion of
the molecule is the more exposed, including the
6-11-S-S- bond possibly involved in hormonal
activity.
The B chain in in the internal portion of the
molecule.
Non covalent binding b/n B chain is respible for
the formation of insulin dimer & higher polymers.

8. Structure of Insulin
Removal of the terminal octapeptide on B chain /
removal of Asn on A chain inactivates insulin.
Removal of terminal carboxy AA of the B chain
and some AAs in the N-ter portion of the
molecule does not affect the activity.
The –OH groups of Ser, Thr can be modified by
sulfation with little loss of potency.
Destruction of His by photo-oxidation results in
complete inactivation.
Increasing iodination of Tyr causes progressive
inactivation.

9. Structure of Insulin
Sulfated bovine insulin, porcine insulin and fish
insulins are sometimes used in the resistant diabetics
because of their reduced antigenicity and cross-
reactivity with circulation antibody.
Other modifications reduce the absorption of insulin
from the injected sites, resulting in prolonging the
axn of insulin.

10. Structure of Insulin
Protamine Zn insulin is a combination of insulin with
protamine which is absorbed more slowly than the
ordinary insulin.
1 injection of protamine Zn insulin may lower the
blood glucose for more than 24hrs, whereas 2or3
injections of regular (crystalline) insulin might be
required for the same effect.

11. Structure of Insulin
Globin insulin , combination with a protein has
an effect of 12-15 hr duration of action
Ultralente insulin is a slow-acting insulin
prepared by controlled crystallization in the
presence of high conc of Zn and acetate in order
to produce large crystals which are therefore
slowly absorbed.
Lente insulin is a 7:3 mixture of ultralente and
regular insulin which has a duration of effect
between the two.