KATP channels and islet hormone secretion: new insights and controversies

KATPchannels have a key role in the regulation of blood glucose homeostasis. This Review outlines their role in the regulation of insulin and glucagon release, which decrease and increase blood glucose levels respectively, under both physiological conditions and in disease states such as diabetes mellitus and hyperinsulinism. ATP-sensitive potassium channels (KATP channels) link cell metabolism to electrical activity by controlling the cell membrane potential. They participate in many physiological processes but have a particularly important role in systemic glucose homeostasis by regulating hormone secretion from pancreatic islet cells. Glucose-induced closure of KATP channels is crucial for insulin secretion. Emerging data suggest that KATP channels also play a key part in glucagon secretion, although precisely how they do so remains controversial. This Review highlights the role of KATP channels in insulin and glucagon secretion. We discuss how KATP channels might contribute not only to the initiation of insulin release but also to the graded stimulation of insulin secretion that occurs with increasing glucose concentrations. The various hypotheses concerning the role of KATP channels in glucagon release are also reviewed. Furthermore, we illustrate how mutations in KATP channel genes can cause hyposecretion or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, and how defective metabolic regulation of the channel may underlie the hypoinsulinaemia and the hyperglucagonaemia that characterize type 2 diabetes mellitus. Finally, we outline how sulphonylureas, which inhibit KATP channels, stimulate insulin secretion in patients with neonatal diabetes mellitus or type 2 diabetes mellitus, and suggest their potential use to target the glucagon secretory defects found in diabetes mellitus.