Insulin

Insulin: synthesis,sectretion,mechanism of action & degradation

1. INSULIN DILSHANA FATHIMA MSc . BIOCHEMISTRY

2. Introduction The endocrinal part of pancreas secretes various types of hormones. These are produced by specialised tissue in the pancreas called islets of langerhans . 4 types of cells are recognised in theses islets A cells ( α cells) : produce glucagon B cells( β cells) : produce insulin D cells( δ cells) : produce somatostatin F cells(PP cells) : produce pancreatic polypeptide

3. Insulin Small polypeptide of mol.wt 5808 Consists of 2 chains : A (21aā) & B (30aā) 2 chains are connected to each other by disulfide linkages An intrachain disulfide connects the 6 th & 11 th aā within the A chain Interchain disulfide connects 7 th aā of A & B chain and b/w 20 th aā of A & 19 th aā of B chain Chemistry

4. Synthesis Insulin is synthesised in the ẞ cells by usual cell machinery for protein synthesis Initially preproinsulin is formed in the ribosomes Cleaved in endoplasmic reticulum to form a proinsulin constiting of 3 chains (A,B & C) most proinsulin is further cleaved in golgi apparatus to form insulin composed of A & B chain connected by disulfide linkages & the c chain peptide called connecting peptide Insulin & c peptide are packed in secretory granules & are secreted in equimolar amounts About 5-10% of final secreted product is still in the form of proinsulin m

5. Secretion The basic cellular mechanism for insulin secretion by β cells is in response to increased blood glucose concentration.

6. Mechanism O f Action Insulin mediates its action through a plasma memberane receptor which has a kinase activity. Insulin receptor consists of 2 α & 2 β subunits. α contain insulin binding site & β contain tyrosine kinase domain. α & β held together by disulfide bonds. Both subunits are glycosylated in nature. α subunits are extracellular β is a transmembrane protein with globular domain at extracellular & cytosolic surfaces

7. Insulin binding to α subunit causes conformational changes in the receptor complex which activates autophosphorylation of β subunit. Once phosphorylated β subunit activates tyrosine kinase which then phosphorylates multiple intracellula proteins incliding insulin receptor substrate 1 (IRS 1) Phosphorylation of IRS 1 generate secondary signals that couple the insulin pathway to transmembrane glucose transport.

8. Degradation Insulin is normally degraded within liver & kidney, having half life of about 5 minutes in human. The major enzyme responsible for insulin degradation is hepatic glutathione insulin dehydrogenase , which disrupts the hormone into individual A & B chain

9. Functions Insulin has anabolic & lipogenic effects Promotes storage of glucose in liver Activates enzymes to prmote glycolusis & glycogenolysis Promote uptake & storage of aminoacids in the form of protein Promote growth Also increases the amount of GLUT-4

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