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

• DOI: 10.1073/pnas.95.18.10402
• Publication Date: 2002-07-26T14:40:11Z
• Authors: Takashi Miki; Kazuaki Nagashima; Fumi Tashiro; Kazumi Kotake; Hideyuki Yoshitomi; Atsuko Tamamoto; Tohru Gonoi; Toshihiko Iwanaga; Jun-ichi Miyazaki; Susumu Seino
• Keywords: Blood Glucose; 0301 basic medicine; Potassium Channels; Tolbutamide; Homozygote; Membrane Potentials; Islets of Langerhans; Mice; 03 medical and health sciences; Glucose; Insulin Secretion; Animals; Insulin; Calcium; Potassium Channels, Inwardly Rectifying; Muscle, Skeletal

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.