Insulin secretion and its chemistry .pptx

about insulin chemistry and its secretion

1. Mechanism of Insulin secretion By - Dr.Upendran Nagappan.D Biochemistry PG 1 st year

2. Introduction An anabolic protein hormone from “Beta cells of Langerhans in pancreas”. First protein hormone to be sequenced, First substance to be measured by radio immune assay (RIA), First compound produced by r-DNA technology for clinical use. It stimulates uptake of glucose into fat, muscles, promote conversion of glucose to glycogen or fat for storage, stimulates protein synthesis. Inhibits protein breakdown, inhibits gluconeogenesis from liver.

3. Chemistry of Insulin A protein hormone with two polypeptide chains, 1) A chain 21 amino acids, 2) B chain 30 amino acids. Molecular weight 5808DA. A to B chain there is 2 disulfide bond, and within A chain there is a disulfide bond.

4. Synthesis Preproinsulin -Protein of about 12000Da, with around 100 amino acid- formed by ribosomes in rough endoplasmic reticulum of beta cells of pancreas. Undetected or rarely found in circulation because of its rapid conversion to Proinsulin (9000Da), (86 amino acid polypeptide). In golgi complex the proinsulin is stored. And here the Proteolytic cleavage happens with the help of Prohormone convertase 1 and pro hormone convertase 2.

5. Proinsulin splitting happens two Ca2+ mediated endopeptidases Major pathway – where PC1 splits Arg 31 and arg 32 at B-C junction, yielding Split-32,33-Proinsulin. followed by removal of exposed molecules yielding – des-31,32-Proinsulin. With help of “Carboxypeptidase H”. following this des-31,32- proinsulin is converted to final product insulin and c peptide by PC2. - 90%of insulin formation happens through this pathway.

6. Insulin secretion Insulin is released in a biphasic fashion . After a glucose load 1 st phase begins in 1 to 2 minutes ends within 10 mins, (stored insulin) Then the 2 nd phase starts where it usually continues till normoglycemic state is achieve which is usually 60-120 minutes. (synthesised insulin) ( in type 2 diabetic individual the 1 st phase is poorly functional or lost but 2 nd phase is preserved) Approximately 40-50U of insulin in secreted per day. Normal fasting insulin ( 5-25 mU /L).

7. Release of insulin Glucose and insulin release-

8. Factors affecting -Release of insulin Factors Stimulation of insulin secretion: Glucose Oestrogen through 17 beta estradiol on “Oestrogen receptor α and β “ over β cells of pancreas. Incretin- Glucagon like peptide-1 (GLP-1) - Glucose dependant insulinotropic polypeptide (GIP) Amino acids, Fatty acids, gastrin, pancreozymin, drugs ( eg : sulfonylureas) Factors Decreasing secretion of insulin : Growth hormone – through phosphodiesterase3B inhibition. Leptin -through phosphodiesterase3B inhibition. Sympathetic activity- cortisol and adrenaline activity.

9. Degradation 50% of insulin extracted by liver and degraded in a first pass through portal circulation. In Kidney- Insulin absorbed through glomeruli reabsorbed and degraded in proximal tubule . Half life of insulin 4-5mins. Proinsulin – has about 10% insulin potency, half life approximately 30mins, degraded by liver. C peptide – 31 amnio acid connecting peptide (c peptide), half life approximately 35mins, degraded by kidneys.

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