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.
- K current