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01.10.2006 | Article

Hyperinsulinism in mice with heterozygous loss of K_ATP channels

verfasst von: M. S. Remedi, J. V. Rocheleau, A. Tong, B. L. Patton, M. L. McDaniel, D. W. Piston, J. C. Koster, C. G. Nichols

Erschienen in: Diabetologia | Ausgabe 10/2006

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Abstract

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 Ca²⁺ 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 ∼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 Ca²⁺ 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.

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Titel: Hyperinsulinism in mice with heterozygous loss of KATP channels
verfasst von: M. S. Remedi
J. V. Rocheleau
A. Tong
B. L. Patton
M. L. McDaniel
D. W. Piston
J. C. Koster
C. G. Nichols
Publikationsdatum: 01.10.2006
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 10/2006
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0367-4

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Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

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