title: Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes.
abstract: Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na(+) channels involved in action potential firing that, via reduced action potential height and Ca(2+) entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.
authors: Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors: Quan
authors: Q
authors: Zhang
authors: Reshma
authors: R
authors: Ramracheya
authors: Carolina
authors: C
authors: Lahmann
authors: Andrei
authors: A
authors: Tarasov
authors: Martin
authors: M
authors: Bengtsson
authors: Orit
authors: O
authors: Braha
authors: Matthias
authors: M
authors: Braun
authors: Melissa
authors: M
authors: Brereton
authors: Stephan
authors: S
authors: Collins
authors: Juris
authors: J
authors: Galvanovskis
authors: Alejandro
authors: A
authors: Gonzalez
authors: Lukas N
authors: LN
authors: Groschner
authors: Nils J G
authors: NJ
authors: Rorsman
authors: Albert
authors: A
authors: Salehi
authors: Mary E
authors: ME
authors: Travers
authors: Jonathan N
authors: JN
authors: Walker
authors: Anna L
authors: AL
authors: Gloyn
authors: Fiona
authors: F
authors: Gribble
authors: Paul R V
authors: PR
authors: Johnson
authors: Frank
authors: F
authors: Reimann
authors: Frances M
authors: FM
authors: Ashcroft
authors: Patrik
authors: P
authors: Rorsman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D005089:Exocytosis; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009154:Mutation; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D014019:Tissue Donors; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium; D015220:Calcium Channels; D005934:Glucagon; D005947:Glucose; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D014044:Tolbutamide; D000099161:Kcnj11 Channel