title: Metabolic and K(ATP) channel-independent actions of keto acid initiators of insulin secretion.
abstract: Insulin-releasing effects of 2-ketobutyric acid (KB), 2-ketoisocaproic acid (KIC), 2-keto-3-methylvaleric acid (KMV), and 3-phenylpyruvic acid (PP) were examined by using clonal beta cells. Whereas KIC, KMV, and PP dose-dependently initiated insulin secretion and potentiated the effects of 4.2-16.7 mM glucose, equimolar KB was without effect. Transport inhibition by using 10 mM valine, isoleucine, 2-cyano-3 hydroxycinnamate or 2-cyano-4 hydroxycinnamate, or metabolic inhibition by 15 mM mannoheptulose, 5 mM sodium azide, 5 mM sodium cyanide, or removal of HCO3 reduced the secretory effects of KIC, KMV, and PP. Whereas K+ depletion reduced keto acid-induced insulin output, depolarizing concentrations of L-leucine and L-arginine potentiated the keto acid-induced effects. Under depolarizing conditions (25 mM KCI and 16.7 mM glucose), 10 mM KIC, KMV, or PP induced insulin secretion, suggesting K(ATP) channel-independent actions. Furthermore, the K(ATP) channel opener diazoxide reduced, but did not abolish, the keto acid-induced effects. However, voltage-dependent Ca2+ channel blockade with verapamil or removal of extracellular Ca2+ abolished keto acid-induced insulin release. Collectively, these results indicate that KIC, KMV, and PP initiate insulin secretion at least partially independently of K(ATP) channel activity, through both mitochondrial metabolism and regulation of Ca2+ influx.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: N H
authors.initials: NH
authors.lastname: McClenaghan
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D003373:Coumaric Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007532:Isoleucine / Q000494:pharmacology; D007651:Keto Acids / Q000494:pharmacology*; D007930:Leucine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology; D010667:Phenylpyruvic Acids / Q000494:pharmacology; D015221:Potassium Channels; D012636:Secretory Rate / Q000187:drug effects; D019810:Sodium Azide / Q000494:pharmacology; D012966:Sodium Cyanide / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014633:Valine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002087:Butyrates; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003373:Coumaric Acids; D007328:Insulin; D007651:Keto Acids; D008565:Membrane Proteins; D010667:Phenylpyruvic Acids; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D007532:Isoleucine; C016211:alpha-keto-beta-methylvaleric acid; C007175:alpha-cyano-4-hydroxycinnamate; C018254:alpha-cyano-3-hydroxycinnamate; C005087:alpha-ketobutyric acid; D001120:Arginine; D019810:Sodium Azide; D014700:Verapamil; D007930:Leucine; D014633:Valine; D005947:Glucose; D003981:Diazoxide; D012966:Sodium Cyanide; D002118:Calcium; C031606:phenylpyruvic acid