ATP-sensitive potassium channels in health and disease.

The ATP-sensitive potassium (K(ATP)) channel plays a crucial role in insulin secretion and thus glucose homeostasis. K(ATP) channel activity in the pancreatic beta-cell is finely balanced; increased activity prevents insulin secretion, whereas reduced activity stimulates insulin release. The beta-cell metabolism tightly regulates K(ATP) channel gating, and if this coupling is perturbed, two distinct disease states can result. Diabetes occurs when the K(ATP) channel fails to close in response to increased metabolism, whereas congenital hyperinsulinism results when K(ATP) channels remain closed even at very low blood glucose levels. In general there is a good correlation between the magnitude of K(ATP) current and disease severity. Mutations that cause a complete loss of K(ATP) channels in the beta-cell plasma membrane produce a severe form of congenital hyperinsulinism, whereas mutations that partially impair channel function produce a milder phenotype. Similarly mutations that greatly reduce the ATP sensitivity of the K(ATP) channel lead to a severe form of neonatal diabetes with associated neurological complications, whilst mutations that cause smaller shifts in ATP sensitivity cause neonatal diabetes alone. This chapter reviews our current understanding of the pancreatic beta-cell K(ATP) channel and highlights recent structural, functional and clinical advances.