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 t he K+ ion-selective pore of the channel. The homozygous mice (Kir6.2(- /-)) lack K-ATP channel activity. Although the resting membrane potent ial and basal intracellular calcium concentrations ([Ca2+](i)) of panc reatic beta cells in Kir6.2(-/-) are significantly higher than those i n control mice (Kir6.2(+/+)), neither glucose at high concentrations n or the sulfonylurea tolbutamide elicits a rise in [Ca2+]i, and no sign ificant insulin secretion in response to either glucose or tolbutamide is found in Kir6.2(-/-), as assessed by perifusion and batch incubati on 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 to lerance test, is increased significantly in Kir6.2(-/-), which could p rotect Kir6.2(-/-) from developing hyperglycemia, Our data indicate th at the K-ATP channel in pancreatic beta cells is a key regulator of bo th glucose- and sulfonylurea-induced insulin secretion and suggest als o that the K-ATP channel in skeletal muscle might be involved in insul in action.