Defective insulin secretion and enhanced insulin action in K(ATP) channel-deficient mice

ATP-sensitive K(+) (K(ATP)) channels regulate many cellular functions by linking cell metabolism to membrane potential. We have generated K(ATP) channel-deficient mice by genetic disruption of Kir6.2, which forms the K(+) ion-selective pore of the channel. The homozygous mice (Kir6.2(−/−)) lack K(ATP) channel activity. Although the resting membrane potential and basal intracellular calcium concentrations ([Ca(2+)](i)) of pancreatic beta cells in Kir6.2(−/−) are significantly higher than those in control mice (Kir6.2(+/+)), neither glucose at high concentrations nor the sulfonylurea tolbutamide elicits a rise in [Ca(2+)](i), and no significant insulin secretion in response to either glucose or tolbutamide is found in Kir6.2(−/−), as assessed by perifusion and batch incubation of pancreatic islets. Despite the defect in glucose-induced insulin secretion, Kir6.2(−/−) show only mild impairment in glucose tolerance. The glucose-lowering effect of insulin, as assessed by an insulin tolerance test, is increased significantly in Kir6.2(−/−), which could protect Kir6.2(−/−) from developing hyperglycemia. Our data indicate that the K(ATP) channel in pancreatic beta cells is a key regulator of both glucose- and sulfonylurea-induced insulin secretion and suggest also that the K(ATP) channel in skeletal muscle might be involved in insulin action.