Sulphonylurea receptor‐1, sulphonylureas and amplification of insulin secretion by E pac activation in β cells

Amplification of insulin secretion by cyclic AMP involves activation of protein kinase A ( PKA ) and E pac2 in pancreatic β cells. Recent hypotheses suggest that sulphonylurea receptor‐1 ( SUR1 ), the regulatory subunit of ATP ‐sensitive potassium channels, is implicated in E pac2 effects and that direct activation of E pac2 by hypoglycaemic sulphonylureas contributes to the stimulation of insulin secretion by these drugs. In the present experiments, using islets from S ur1 KO mice, we show that dibutyryl‐ cAMP and membrane‐permeant selective activators of E pac or PKA normally amplify insulin secretion in β cells lacking SUR1 . In contrast to E pac activator, sulphonylureas (glibenclamide and tolbutamide) did not increase insulin secretion in S ur1 KO islets, as would be expected if they were activating E pac2 directly. Furthermore, glibenclamide and tolbutamide did not augment the amplification of insulin secretion produced by E pac activator or dibutyryl‐ cAMP . Collectively, the results show that SUR1 is dispensable for amplification of insulin secretion by E pac2 activation and that direct activation of E pac2 is unimportant for the action of therapeutic concentrations of sulphonylureas in β cells.