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.