Glucagon antagonists for the treatment of Type 2 diabetes

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Abstract
Insulin and glucagon are the primary agents responsible for ensuring acute and long-term maintenance of glucose levels in the blood. There is strong evidence that excessive glucagon levels contribute to the hyperglycaemia of non-insulin dependent diabetes mellitus (NIDDM) by inappropriately stimulating hepatic glucose output in both fasting and fed states. The blocking of glucagon binding to its receptor was therefore considered a novel approach to reducing plasma glucose levels. Early efforts to prepare glucagon antagonists focused on peptidic analogues of glucagon. More recently, a number of small molecule glucagon antagonists have been reported which were obtained through high-throughput screening (HTS) of small molecule libraries. The historical work involving peptidic antagonists is reviewed first, followed by a review of the more recent developments with non-peptidic antagonists. The first small molecule antagonist from Bayer has just entered clinical trials. It is anticipated that this and future c...