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.

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.

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.

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.