ATP-sensitive potassium channels in health and disease

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