title: Glucose and non-glucidic nutrients exert permissive effects on 2-keto acid regulation of pancreatic beta-cell function.
abstract: Insulin-releasing effects of straight and branched chain 2-keto acids were assessed using clonal glucose-responsive beta-cells. Pyruvic acid (PA), 2-ketovaleric acid (KV), 2-ketoisovaleric acid (KIV) or 2-keto-3-methylvaleric acid (KMV) dose-dependently promoted the stimulatory effects of D-glucose, whereas 2-ketobutyric acid (KB) did not affect insulin release. The stimulatory 2-keto acids also promoted the stimulatory activity of D-glyceraldehyde, L-leucine or L-arginine. Responses to PA, KV, KIV or KMV were significantly reduced by transport inhibition with 2-cyano-3 hydroxycinnamate, glucokinase inhibition with mannoheptulose or metabolic inhibition with sodium azide or sodium cyanide. Membrane hyperpolarisation with K+ depletion or diazoxide reduced insulin output, but failed to abolish secretory responses to KV, KIV and KMV. Secretory effects of these 2-keto acids also persisted in beta-cells depolarised with high KCl and glucose. Voltage-dependent Ca2+ channel blockade, with verapamil, or depletion of extracellular Ca2+ abolished the secretory activity of 2-keto acids. Collectively, these results indicate that glucose and metabolisable nutrients exert permissive effects on 2-keto acid-induced insulin release. In addition, KV, KIV and KMV can regulate beta-cell function at least partially independently of K+-ATP channel activity, both through their mitochondrial metabolism and regulation of Ca2+ influx.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK. nh.mcclenaghan@ulst.ac.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; D002999:Clone Cells; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007651:Keto Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats
chemical_list: D007328:Insulin; D007651:Keto Acids; D005947:Glucose