Progress towards glucagon receptor antagonist therapy for Type 2 diabetes

摘要

Peptidal glucagon receptor antagonists and antiglucagon monoclonal antibodies lower glucose levels in diabetic rodent models, suggesting a potential to treat hyperglycaemia in Type 2 diabetics through the inhibition of glucagon function. Several research groups have discovered small molecule glucagon antagonists from multiple chemical series and at least one has been clinically evaluated. Although multiple compounds have blocked the rise in blood glucose levels in response to a glucagon challenge, no preclinical or clinical efficacy data from chronic studies have been reported. In general, drug candidate potency, pharmacokinetics, physical properties and cross-species potency have hindered progress and preclinical efficacy assessment. Recently, antisense oligonucleotides against the glucagon receptor have been described, providing a guiding post for the type of activity a small molecule glucagon antagonist may possess, as well as offering a potential therapeutic strategy.