Role of KATP channels in insulin secretion. (a) When metabolism is low, KATP channels are open, keeping the membrane hyperpolarized and voltage-gated Ca2+ channels closed, so that [Ca2+]i remains low and insulin secretion is prevented. (b) When metabolism increases, ATP increases and MgADP falls, closing KATP channels. This triggers depolarization of the β-cell, opening voltage-gated Ca2+ channels, and initiating Ca2+ influx and insulin release. (c) Loss-of-function mutations in SUR1 cause HI by producing permanent KATP channel closure, continuous membrane depolarization and Ca2+ influx, and thus persistent insulin secretion. (d) Gain-of-function mutations in SUR1 result in a failure of KATP channel closure when metabolism rises, so that the β-cell remains hyperpolarized even when blood glucose levels are elevated, keeping voltage-gated Ca2+ channels closed and preventing insulin secretion. This leads to diabetes.