alpha2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice.

Background and purpose:The imidazoline-type α₂-adrenoceptor antagonists (±)-efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic β-cell α₂-adrenoceptors or by α₂-adrenoceptor-independent mechanisms. Many imidazolines inhibit the pancreatic β-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, α_2A-adrenoceptor knockout (α_2A-KO) mice were used.Experimental approach:Effects of (±)-efaroxan, 5 mg kg⁻¹, and phentolamine, 1 mg kg⁻¹, on blood glucose and insulin levels were compared with those of the non-imidazoline α₂-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), 1 mg kg⁻¹, and the sulphonylurea glibenclamide, in α_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 α_2A-KO mice, (±)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted α_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 α_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 β-cell α_2A-adrenoceptors, and demonstrate a critical role for α_2A-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.British Journal of Pharmacology (2008) 154, 1287–1296; doi:10.1038/bjp.2008.186; published online 19 May 2008 [ABSTRACT FROM AUTHOR]