Sulphonylurea receptor-1, sulphonylureas and amplification of insulin secretion by Epac activation in β cells.

Amplification of insulin secretion by cyclic AMP involves activation of protein kinase A (PKA) and Epac2 in pancreatic β cells. Recent hypotheses suggest that sulphonylurea receptor-1 (SUR1), the regulatory subunit of ATP-sensitive potassium channels, is implicated in Epac2 effects and that direct activation of Epac2 by hypoglycaemic sulphonylureas contributes to the stimulation of insulin secretion by these drugs. In the present experiments, using islets from Sur1KO mice, we show that dibutyryl-cAMP and membrane-permeant selective activators of Epac or PKA normally amplify insulin secretion in β cells lacking SUR1. In contrast to Epac activator, sulphonylureas (glibenclamide and tolbutamide) did not increase insulin secretion in Sur1KO islets, as would be expected if they were activating Epac2 directly. Furthermore, glibenclamide and tolbutamide did not augment the amplification of insulin secretion produced by Epac activator or dibutyryl-cAMP. Collectively, the results show that SUR1 is dispensable for amplification of insulin secretion by Epac2 activation and that direct activation of Epac2 is unimportant for the action of therapeutic concentrations of sulphonylureas in β cells.