title: Insulin secretion and its modulation by antiarrhythmic and sulfonylurea drugs.
abstract: Cardiovascular drugs such as antiarrhythmic agents with Vaughan Williams class Ia action have been found to induce a sporadic hypoglycemia. Recent investigation has revealed that these drugs induce insulin secretion from pancreatic beta-cells by inhibiting ATP-sensitive K+ (KATP) channels in a manner similar to sulfonylurea drugs. The mechanism underlying block of KATP channels by antiarrhythmic drugs was different, however, from that of sulfonylureas: firstly, because binding of radioactive glibenclamide could not be inhibited by unlabelled antiarrhythmic agents, and vice versa; secondly, because the two compounds differ in the kinetics and sidedness of drug action-antiarrhythmic drugs act on the channel from the inner surface of the cell membrane, whereas glibenclamide binds through the intramembrane pathway; finally, it was shown that functional KATP channels in beta-cells are composed of two distinct molecules-a sulfonylurea receptor (SUR) and a channel pore-forming subunit, an inwardly-rectifying K channel with two transmembrane regions (Kir6.2). Antiarrhythmic drugs reversibly inhibit the K+ conductance displayed by the Kir6.1 (a putative KATP channel clone)-transfected NIH3T3 cells. Therefore they appear to interact directly with the pore-forming subunit, thereby inhibiting KATP channel currents and exerting an insulinotrophic effect.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan. horie@kuhp.kyoto-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Horie
authors.forename: A
authors.initials: A
authors.lastname: Ishida-Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Ai
authors.forename: T
authors.initials: T
authors.lastname: Nishimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuura
authors.forename: H
authors.initials: H
authors.lastname: Ishida
authors.forename: Y
authors.initials: Y
authors.lastname: Seino
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D016475:3T3 Cells; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors