α2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

Background and purpose: The imidazoline-type alpha(2)-adrenoceptor antagonists (+/-)-efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic beta-cell alpha(2)-adrenoceptorsor by alpha(2)-adrenoceptor-independent mechanisms. Many imidazolines inhibit the pancreatic beta-cell K(ATP) channel, which is the molecular target of sulphonylurea drugs used in the treatment of type II diabetes. To investigate the mechanisms of action of (+/-)-efaroxan and phentolamine, alpha(2A)-adrenoceptor knockout (alpha(2A)-KO) mice were used. Experimental approach: Effects of (+/-)-efaroxan, 5mg kg(-1), and phentolamine, 1mg kg(-1), on blood glucose and insulin levels were compared with those of the non-imidazoline alpha(2)-adrenoceptor antagonist [8aR, 12aS, 13aS]-5,8,8a, 9,10,11, 12,12a, 13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6] naphthyridine (RS79948- 197), 1mg kg(-1), and the sulphonylurea glibenclamide, in alpha(2A)-KO and control (wild type (WT)) mice. Key results: In fed WT mice, (+/-)-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed alpha(2A)-KO mice, (+/-)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted alpha(2A)-KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg(-1)), caused severe hyperinsulinaemia and hypoglycaemia in alpha(2A)-KO mice. This was mimicked in WT mice by co-administration of RS79948- 197 with glibenclamide. Conclusions and implications: These results suggest that (+/-)-efaroxan and phentolamine increase insulin secretion by inhibition of beta-cell alpha(2A)-adrenoceptors, and demonstrate a critical role for alpha(2A)-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.