Defective insulin secretion and enhanced insulin action in KATP 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 the K + ion-selective pore of the channel. The homozygous mice (Kir6.2 −/− ) lack K ATP c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-09, Vol.95 (18), p.10402-10406
Main Authors: Miki, T, Nagashima, K, Tashiro, F, Kotake, K, Yoshitomi, H, Tamamoto, A, Gonoi, T, Iwanaga, T, Miyazaki, J, Seino, S
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biological Sciences
Blood Glucose - metabolism
Calcium - metabolism
Cellular biology
Glucose - pharmacology
Homozygote
Insulin
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
Rodents
Tolbutamide - pharmacology
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Summary: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. sulfonylurea receptor/inward rectifier/gene targeting
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.18.10402