Glucagon antagonists open a new way in treatment of type 2 diabetes Mellitus

Authors: Karel Vondra
Authors‘ workplace: Endokrinologický ústav, Praha
Published in: Vnitř Lék 2016; 62(7-8): 661-666
Category: Reviews


Excessive hepatic glucose production resulting from dysregulated glucagon secretion associated with inappropriate fasting and postprandial hyperglucagonemia is common feature in type 2 diabetes (DM2T). The effects of some currently widely used anti-diabetic agents, especially concerning metformin, GLP1 agonists and inhibitors of DPP4, comprise partial supression of glucagon secretion and/or action. Complete supression of glucagon action is recently widely investigated in experiments, and also results of phase 1 and 2 of the clinical trials are available. The experimental studies proved expected therapeutical potential of this approach. Blockade of glucagon action in diabetic animals resulted in decreased hepatic glucose production, reduction of fasting and prandial hyperglycemia, and improved glucose tolerance. On the other hand, the complete supression of glucagon action is associated with possible risk of pancreatic A-cell hyperplasia, hyperglucagonemia, increased sensitivity to the development of liver steatosis or other liver damage, higher risk of hypoglycemia and other potential side effects. Thus evaluation of safety profile must represent the high priority in the development of new molecules affecting glucagon secretion and intracellular action. A number of molecules antagonising glucagon action were prepared in recent years; some of them are already reviewed successfully in phase 2 of clinical testing; however no molecule is used in clinical practice so far. The presented article briefly sums up contemporary knowledge about glucagon dysregulation in T2DM, and gained experience with pharmacological supression of glucagon action in those patients. Anti-sense oligo-nucleotides, and monoclonal anti-bodies against glucagon and glucagon receptor are mentioned. The glucagon receptor antagonists are discussed in a greater detail as well.

Key words:
glucagon antagonism – potential side effects – type 2 diabetes mellitus


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