Membrane Ion Channels and Diabetes

P.      Proks; J.   D.   Lippiat

Abstract

Type-2, or non-insulin-dependent diabetes mellitus is a serious disease that is now widespread throughout Western society. Glucose intolerance, or failure of glucose to stimulate insulin secretion, is a primary factor in the manifestation of this disease and is likely to be due to the failure of glucose metabolism to stimulate pancreatic βcell electrical activity, calcium influx, and insulin secretion. In this review we describe how ion channels regulate the electrical behaviour of the βcell and how the membrane potential depolarises in response to a rise in glucose metabolism. Central to these electrical events is the inhibition of ATP-sensitive potassium channel by ATP, and we summarise recent advances in our understanding of the properties of this ion channel in coupling βcell metabolism to electrical activity. We discuss the mechanism, specificity, and clinical implications of the pharmacological inhibition of KATP channels by sulphonyureas and other antidiabetic drugs. The roles of other ion channels in regulating electrical activity are considered, and also their potential use as targets for drug action in treating βcell disorders.

Keywords: Pancreatic βcell, insulin secretion, KATP channel, sulphonylureas, type-2 diabetes, metabolism, permanent neonatal diabetes, persistent hyperinsulinaemia, hyperglycaemia