INSULIN ANTAGONISTS

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INSULIN ANTAGONISTS Insulin is a two chain polypeptide having 51 amino acids with a molecular weight of 5808.The A and B chain are linked by a disulfide bonds with A having 21 amino acids and B 31 am ... ino acids.Proinsulin, a long single chain protein molecule, is processed within the Golgi apparatus and packaged into granules where it is hydrolyzed into insulin and the C-peptide by removal of four amino acids. Regulation of insulin secretion from the pancreas is regulated by three mechanisms that include: chemical, hormonal and neural mechanisms.Chemicaly is by the glucose transporter (GLUT1) and its phosphorylation by glucokinase.Hormonal regulation is through growth hormone, thyroxine hormone and corticosteroids that modify insulin release in response to glucose.Somatostatin inhibit both release of insulin and glucagon. Glucagon evokes release of insulin as well as somatostatin.Neural regulation is by the sympathetic and vagal nerves. Adrenergic α2 receptor activation decreases insulin release by inhibiting β cell adenylyl cyclase.Stimulation of β2 and cholinergic receptors increase insulin secretion. History of insulin and insulin antagonists Insulin was discovered in 1921 by Banting and Best who demonstrated the hypoglycemic action of an extract of pancreas prepared after degeneration of the exocrine part due to ligation of the pancreatic duct. Two years after the discovery of insulin, glucagon was discovered by demonstrating a hyperglycemic principle was demonstrated to be present in the islets Individual molecules I. Glucagon Is a single chain polypeptide containing 29 amino acids secreted by the cells of the islets of Langerhans .It is produced commercially by recombinant DNA technology? Regulation of secretion is through the glucose levels, other nutrients, paracrine hormones and the nervous system. Glucagon is a hyperglycemic and its actions are opposite to that of insulin. Glucagon enhances glycogenolysis and gluconeogenesis in the liver and suppression of glucose utilization in the muscle and fat. It is considered as a hormone of fuel mobilization. II. Somatostatin Recombinant Somatostatin is a peptide chemically similar to endogenous somatostatin.It causes hyperglycemia by primarily inhibiting release of insulin. III. Thiazides Thiazides are sulfonamide related organic acids that share common benzothiadiazine ring .These agents inhibit insulin secretion as well as well glucose uptake by tissues. IV. Diazoxide It is a benzothiadiazine that has a chemical resemblance to thiazides. It causes peripheral vasodilation.It increases the concentration of glucose in plasma and inhibits the secretion of insulin from the β cells. V. Streptozocin It is a methylnitrosourea antineoplastic antibiotic isolated from bacterium Streptomyces achromogenes.Due to its glucose moiety; it is readily taken up by the pancreatic beta cells inducing hyperglycemia at high concentrations. MECHANISM OF ACTION OF INSULIN ANTAGONISTS a) GLUCAGON Glucagon binds to the G-protein coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates G protein. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule. This substitution results in the releasing of the subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase. Adenylate cyclase manufactures cyclic adenosine monophosphate, which activates protein kinase A. This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b, converting it into the active form phosphorylase a. Phosphorylase is responsible for the release of glucose 1-phosphate from glycogen polymers. The enzyme protein kinase that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing the enzymes fructose 2, 6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2, 6-bisphosphate by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon. Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes. b) DIAZOXIDE Diazoxide is an effective and relatively long-acting potassium channel opener that causes hyperpolarization in smooth muscle and pancreatic β cells. Because of its arteriolar dilating property, it was formerly used parenterally to treat hypertensive emergencies. Diazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the beta cell membrane). Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. Diazoxide is partially metabolized; its metabolic pathways are not well characterized. c) THIAZIDE DIURETICS Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+ /Cl- transporter. They actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+reabsorption. In the DCT, lowering of intracellular Na+by thiazide-induced blockade of Na+ [Show More]

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