title: Diabetes and insulin secretion: the ATP-sensitive K+ channel (K ATP) connection.
abstract: The ATP-sensitive K+ channel (K ATP channel) senses metabolic changes in the pancreatic beta-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When K ATP channels open, beta-cells hyperpolarize and insulin secretion is suppressed. The prediction that K ATP channel "overactivity" should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating "activating" mutations in the Kir6.2 subunit of K ATP channel as causal in human diabetes. This article summarizes the emerging picture of K ATP channel as a major cause of neonatal diabetes and of a polymorphism in K ATP channel (E23K) as a type 2 diabetes risk factor. The degree of K ATP channel "overactivity" correlates with the severity of the diabetic phenotype. At one end of the spectrum, polymorphisms that result in a modest increase in K ATP channel activity represent a risk factor for development of late-onset diabetes. At the other end, severe "activating" mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting K ATP channel "overactivity" in both pancreatic and extrapancreatic tissues.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. jkoster@cellbio.wustl.edu
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Koster
authors.forename: M Alan
authors.initials: MA
authors.lastname: Permutt
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D009154:Mutation / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D000255:Adenosine Triphosphate