Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of alpha(2A)-adrenergic antagonism in the treatment of type 2 diabetes?

作者：Lehner Z; Stadlbauer K; Adorjan I; Rustenbeck I; Belz M; Fenzl A; de Cillia V A M; Gruber D; Bauer L; Frobel K; Brunmair B; Luger A; Fuernsinn C^*

来源：Diabetologia, 2012, 55(11): 3071-3082.

DOI：10.1007/s00125-012-2679-x

• alpha(2A)-Adrenoceptor
• Efaroxan
• Glucose tolerance
• Imidazoline
• Insulin secretion
• Islets
• K-ATP channel
• Mice

Inspired by recent speculation about the potential utility of alpha(2A)-antagonism in the treatment of type 2 diabetes, the study examined the contribution of alpha(2)-antagonism vs other mechanisms to the antihyperglycaemic activity of the imidazoline (+/-)-efaroxan. %26lt;br%26gt;Effects of the racemate and its pure enantiomers on isolated pancreatic islets and beta cells in vitro, as well as on hyperglycaemia in vivo, were investigated in a comparative manner in mice. %26lt;br%26gt;In isolated perifused islets, the two enantiomers of efaroxan were equally potent in counteracting inhibition of insulin release by the ATP-dependent K+ (K-ATP) channel-opener diazoxide but (+)-efaroxan, the presumptive carrier of alpha(2)-antagonistic activity, was by far superior in counteracting inhibition of insulin release by the alpha(2)-agonist UK14,304. In vivo, (+)-efaroxan improved oral glucose tolerance at 100-fold lower doses than (-)-efaroxan and, in parallel with observations made in vitro, was more effective in counteracting UK14,304-induced than diazoxide-induced hyperglycaemia. The antihyperglycaemic activity of much higher doses of (-)-efaroxan was associated with an opposing pattern (i.e. with stronger counteraction of diazoxide-induced than UK14,304-induced hyperglycaemia), which implicates a different mechanism of action. %26lt;br%26gt;The antihyperglycaemic potency of (+/-)-efaroxan in mice is almost entirely due to alpha(2)-antagonism, but high doses can also lower blood glucose via another mechanism. Our findings call for reappraisal of the possible clinical utility of alpha(2A)-antagonistic compounds in recently identified subpopulations of patients in which a congenitally higher level of alpha(2A)-adrenergic activation contributes to the development and pathophysiology of type 2 diabetes.

• 出版日期2012-11