Hyperinsulinism in mice with heterozygous loss of K(ATP) channels.

Remedi MS, Rocheleau JV, Tong A, Patton BL, McDaniel ML, Piston DW, Koster JC, Nichols CG
Diabetologia. 2006 49 (10): 2368-78

PMID: 16924481 · DOI:10.1007/s00125-006-0367-4

AIMS/HYPOTHESIS - ATP-sensitive K(+) (K(ATP)) channels couple glucose metabolism to insulin secretion in pancreatic beta cells. In humans, loss-of-function mutations of beta cell K(ATP) subunits (SUR1, encoded by the gene ABCC8, or Kir6.2, encoded by the gene KCNJ11) cause congenital hyperinsulinaemia. Mice with dominant-negative reduction of beta cell K(ATP) (Kir6.2[AAA]) exhibit hyperinsulinism, whereas mice with zero K(ATP) (Kir6.2(-/-)) show transient hyperinsulinaemia as neonates, but are glucose-intolerant as adults. Thus, we propose that partial loss of beta cell K(ATP) in vivo causes insulin hypersecretion, but complete absence may cause insulin secretory failure.

MATERIALS AND METHODS - Heterozygous Kir6.2(+/-) and SUR1(+/-) animals were generated by backcrossing from knockout animals. Glucose tolerance in intact animals was determined following i.p. loading. Glucose-stimulated insulin secretion (GSIS), islet K(ATP) conductance and glucose dependence of intracellular Ca(2+) were assessed in isolated islets.

RESULTS - In both of the mechanistically distinct models of reduced K(ATP) (Kir6.2(+/-) and SUR1(+/-)), K(ATP) density is reduced by approximately 60%. While both Kir6.2(-/-) and SUR1(-/-) mice are glucose-intolerant and have reduced glucose-stimulated insulin secretion, heterozygous Kir6.2(+/-) and SUR1(+/-) mice show enhanced glucose tolerance and increased GSIS, paralleled by a left-shift in glucose dependence of intracellular Ca(2+) oscillations.

CONCLUSIONS/INTERPRETATION - The results confirm that incomplete loss of beta cell K(ATP) in vivo underlies a hyperinsulinaemic phenotype, whereas complete loss of K(ATP) underlies eventual secretory failure.

MeSH Terms (15)

Animals ATP-Binding Cassette Transporters Blood Glucose Hyperinsulinism Insulin Insulin Secretion Kinetics Loss of Heterozygosity Mice Mice, Knockout Multidrug Resistance-Associated Proteins Potassium Channels Potassium Channels, Inwardly Rectifying Receptors, Drug Sulfonylurea Receptors

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