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Hormones of gastrointestinal tract

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Text of Hormones of gastrointestinal tract

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

2. The acinar portion of pancreas has exocrine function . Endocrine portion consists of islets of langerhans. 3. Insulin is hetero dimeric polypeptide . Insulin gene is located on short arm of chromosome 11 . Insulin is synthesized as a preproinsulin ( 86 AA) . 4. The location of 3 disulfide bonds is invarient & the A & B chains have 21 & 30 amino acids respectively in most species . 5. Substitutions occur commonly at 8 , 9 , 10 positions of the A chain thus this region is not crucial for bioactivity . 6. Zinc is present in high concentrations in B cell & forms complexes with insulin & proinsulin . 7. The proinsulin molecule undergoes a series of site specific peptide cleavages that results in formation of equimolar amounts of mature insulin & C peptide . Mature insulin & C peptide are present together in the secretory granule . 8. C peptide is less susceptible than insulin to hepatic degrdation , & it is a distinct molecule from an antigenic stand point . 9. Glucose level more than 70mg/dl stimulates insulin synthesis , primarily by enhancing protein translation & processing . 10. Glucose is the key regulator of insulin secretion . 11. Elevated plasma arginine is a potent stimulus for insulin synthesis & secretion . The intestinal peptides cholecystokinin & gastric inhibitory polypeptide increase insulin secretion in response to oral glucose & so are referred to as incretins . Chronic exposure to excessive levels of GH , cortisol, placental lactogen , estrogen & progestins increase insulin secretion . 12. The synthesis & release of insulin are decreased when there is scarcity of dietary fuels & also during periods of stress . Alpha adrenergic agonist principally epinephrine , inhibits insulin release even when this process was stimulated by glucose . Beta adrenergic agonists stimulate insulin release , probably by increasing the intracellular c AMP . 13. Plasma half life of insulin is 3 5 minutes under normal conditions . The major organs involved in insulin metabolism are liver , kidney & the placenta . Insulin specific protease & hepatic glutathione transhydrogenase are involved in degradation of insulin . 14. Effect on membrane transport : insulin promotes glucose entry into muscle & adipose tissue . 15. The transporter translocation is temperature & energy dependent & is protein synthesis independent . 16. Insulin promotes amino acid entry into cells particularly in muscle & enhances the movement of K+ , Ca ++ , nucleotides , & inorganic phosphate . These effects are independent of action of glucose entry . 17. Insulin increases hepatic glycolysis by increasing the activity & amount of glucokinase , phosphofructokinase , & pyruvate kinase . 18. Insulin decreases the activity of glucose 6 phosphatse , an enzyme found in liver not in muscle. In skeletal muscle insulin stimulates glucose entry through transporters & also increases hexokinase II 19. Insulin stimulates lipogenesis in adipose tissue . 1. By providing acetyl CoA & NADPH required for fatty acid synthesis . 2. By maintaining normal level of enzyme acetyl CoA carboxylase & 3. By providing glycerol involved in the TAG synthesis . 20. Lipogenesis is decreased in insulin deficiency . Increased fatty acids in circulation due to several hormones unopposed action by insulin . Free fatty acids feed back inhibit their own synthesis by inhibiting acetyl CoA carboxylase . Free fatty acids inhibit glycolysis at several steps & stimulates gluconeogenesis . 21. In liver & muscle insulin stimulates conversion of glucose to glucose 6 phosphate ( by the actions of glucokinase & hexokinase II resepectively . Glucose 6 phosphate is isomerized to glucose 1 phosphate & is incorporated into glycogen . Glycogen synthase is stimulated by insulin . Insulin inhibits the enzyme phosphorylase . The net effect of insulin on glycogen metabolism is anabolic . 22. Effect on glucose production : insulin decreases the key gluconeogenic enzyme phospho enol pyruvate carboxy kinase ( PEPCK ) by selectively inhibiting transcription of gene that codes for mRNA for PEPCK . 23. Effects on lipid metabolism : insulin is a potent inhibitor of lipolysis in liver & adipose tissue . The above action is due to its ability to decrease cAMP levels by activating phosphodiesterases . Insulin inhibits hormone sensitive lipase by the action of phosphatase . Insulin affects the formation or clearance of VLDL & LDL . 24. Effects on protein metabolism : insulin promote protein synthesis & retards protein degradation . The effect of insulin on protein synthesis in skeletal & cardiac muscle & in liver are thought to be exerted at the level of mRNA translation . Insulin shown to influence the synthesis of specific proteins by effecting changes in corresponding mRNAs. 25. Insulin activates a protein kinase path way that results in activation of eIF 4E , a factor essential for the rate limiting step in protein synthesis . 26. The regulation of mRNA synthesis is a major action of insulin Insulin decrease transcription of PEPCK gene leading to decreased amount of primary transcript & of mature mRNA . More than 100 specifc mRNA by insulin. 27. Effects on cell replication : insulin stimulates the proliferation of number of cells in culture & it may also be involved in the regulation of growth invivo . Insulin potentiats the ability of 1. Fibroblast growth factor , 2. PDFG 3. EGF 4. Tumor promoting phorbol esters 5. PGF2 alpha 6. Vasopressin & cAMP analougues 28. Insulin receptor along with PDGF & EGF has tyrosine kinase activity . oncogene products involved in stimulating malignant cell replication are also tyrosine kinases. Mammalian cells contain analogs of these oncogenes ( protooncogenes ) which may be involved in the replication of normal cells . Expression of two protooncogene products , c fos , c myc increases following addition of insulin & PDGF to growth arrested cells . 29. Glucagon is synthesized as precursor molecule. Half life of glucagon is 5 minutes . Glucagon is inactivated by liver an enzyme removes 1st 2 aminoacids from the amino terminal end by cleaving Ser 2 & Gln 3 . Secretion of glucagon is inhibited by glucose . Glucagon binds to specific receptors & activates adenylyl cyclase through G protein linked mechanism . 30. The cAMP activates phosphorylase , which enhances glycogenolysis while inhibiting glycogen synthase enzyme . Glucagon through cAMP , increase the rate of transcription of mRNA from PEPCK gene & stimulates synthesis of more PEPCK . PEPCK is the rate limiting enzyme gluconeogenic pathway . Glucagon is a potent lipolytic agent , it increases adipose cell cAMP & this activates hormone sensitive lipase . 31. D cells of islets synthesize large somatostatin prohormone . The rate of transcription of prosomatostatin is gene is markedly increased by enhanced cAMP . Somatostatin inhbits the release other islet cell hormones through a paracrine action . In CNS it acts as neurotransmitter , in GIT it decreases the delivery of nutrients into the circulation . 32. Two families of GI horomones gastrin family & secretin family . Gastrin family consists of gastrin & cholecystokinin . Secretin family includes secretin , glucagon , gastric inhibitory polypeptide (GIP ) , Vasoactive intestinal peptides .