Farooq Ahmad Khan, Abdul Khaliq Naveed.
Regulation of glucagon, somatostatin and GLP-1 by insulin and forskolin in rats.
J Coll Physicians Surg Pak Jan ;12(1):4-11.

Objective: Glucagon had stimulatory effect on insulin secretion and insulin inhibits glucagon release. The possible mechanism of insulin effect on proglucagon gene transcription under physiological conditions has to be established. Conflicting reports exist regarding signal pathway involved in the regulation of islet and intestinal glucagon producing cells, therefore, present study was designed to determine the in-vivo effect of insulin and forskolin on glucagon. Design : Prospective and experimental study. Place and Duration of Study: The study was conducted in the Department of Chemical Pathology & Endocrinology, Armed Forces Institute of Pathology, Rawalpindi. Laboratory facilities of the Department of Metabolic Medicine, Hammersmith Hospital, London were used for specialized procedures. The study was completed in one year. Subjects and Methods: An in-vivo study was conducted by producing hyperinsulinaemic, isoglycaemic clamp. Forskolin, which is a direct activator of adenylate cyclase system, was infused to diabetic rats to establish the second messenger involved in the regulation of islets cell function and intestinal glucagon gene transcription. Results: Insulin decreased glucagon secretion and its mRNA in rats infused with insulin as compared to controls. Plasma levels of glucagon was more in diabetic as compared to non diabetic control rats. It is interpreted that glucagon mRNA in diabetic controlled rats will also be more as compared to normal controlled rats. GLP-1 level in diabetic controls was more as compared to non diabetic controls indicating loss of inhibitory effect on intestinal glucagon by insulin in diabetics. Insulin infusion significantly decreased GLP-1 levels in diabetic rats. Forskolin did not affect the glucagon secretion or its mRNA in pancreas but it increased GLP-1 levels in plasma of rats. Somatostatin levels decreased by insulin and a significant hypersomatostatinemia was observed in diabetic controls as compared to non diabetic control rats. Forskolin increased somatostatin and insulin secretions. Concentrations of insulin were significantly high (about 10 times) as compared to controls in rats infused with insulin. Conclusion: It is concluded that insulin normalizes hyperglucagonemia in diabetics by exerting its effects at gene transcription level. Insulin also negatively regulates intestinal proglucagon gene. Somatostatin is negatively regulated by insulin. The cAMP dependent pathway may be involved in the regulation of glucagon gene in intestine. Pancreatic B and D cells are stimulated by cAMP dependent pathway. The increased insulin, somatostatin and GLP-1 in response to forskolin may have masked the effect of forskolin on A cells, due to which no effect on glucagon secretion and synthesis was observed.

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