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

Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10402-6. doi: 10.1073/pnas.95.18.10402.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Calcium / metabolism
  • Glucose / pharmacology
  • Homozygote
  • Insulin / metabolism*
  • Insulin / physiology
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Membrane Potentials
  • Mice
  • Muscle, Skeletal / metabolism
  • Potassium Channels / genetics
  • Potassium Channels / physiology*
  • Potassium Channels, Inwardly Rectifying*
  • Tolbutamide / pharmacology

Substances

  • Blood Glucose
  • Insulin
  • Kcnj1 protein, mouse
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Tolbutamide
  • Glucose
  • Calcium