Hyperinsulinism in mice with heterozygous loss of KATP channels

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.