Defective insulin secretion and enhanced insulin action in KATP 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 ([Ca2+](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 [Ca2+]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.