Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice

T Miki, K Nagashima, F Tashiro… - Proceedings of the …, 1998 - National Acad Sciences
T Miki, K Nagashima, F Tashiro, K Kotake, H Yoshitomi, A Tamamoto, T Gonoi, T Iwanaga…
Proceedings of the National Academy of Sciences, 1998National Acad Sciences
ATP-sensitive K+ (KATP) channels regulate many cellular functions by linking cell
metabolism to membrane potential. We have generated KATP 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 KATP 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 …
ATP-sensitive K+ (KATP) channels regulate many cellular functions by linking cell metabolism to membrane potential. We have generated KATP 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 KATP 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 KATP channel in pancreatic beta cells is a key regulator of both glucose- and sulfonylurea-induced insulin secretion and suggest also that the KATP channel in skeletal muscle might be involved in insulin action.
National Acad Sciences