Hyperinsulinism in mice with heterozygous loss of KATP channels

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

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Aims/hypothesis: ATP-sensitive K+ (KATP) channels couple glucose metabolism to insulin secretion in pancreatic beta cells. In humans, loss-of-function mutations of beta cell KATP 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 KATP (Kir6.2[AAA]) exhibit hyperinsulinism, whereas mice with zero KATP (Kir6.2-/-) show transient hyperinsulinaemia as neonates, but are glucose-intolerant as adults. Thus, we propose that partial loss of beta cell KATP 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 KATP conductance and glucose dependence of intracellular Ca2+ were assessed in isolated islets. Results: In both of the mechanistically distinct models of reduced KATP (Kir6.2+/- and SUR1+/-), KATP 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 KATP in vivo underlies a hyperinsulinaemic phenotype, whereas complete loss of K ATP underlies eventual secretory failure.

Original languageEnglish
Pages (from-to)2368-2378
Number of pages11
JournalDiabetologia
Volume49
Issue number10
DOIs
StatePublished - Oct 1 2006

Keywords

  • ABCC8
  • Hyperinsulinism
  • K
  • K current
  • KCNJ11
  • Kir6.2
  • Knockout
  • Mice
  • Pancreas
  • SUR1

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