Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice.
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.
Department of Molecular Medicine, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba 260, Japan.
T
T
Miki
K
K
Nagashima
F
F
Tashiro
K
K
Kotake
H
H
Yoshitomi
A
A
Tamamoto
T
T
Gonoi
T
T
Iwanaga
J
J
Miyazaki
S
S
Seino
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006720:Homozygote; D007328:Insulin / Q000378:metabolism* / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D014044:Tolbutamide / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; C510693:Kcnj1 protein, mouse; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D014044:Tolbutamide; D005947:Glucose; D002118:Calcium