Glucose and non-glucidic nutrients exert permissive effects on 2-keto acid regulation of pancreatic β-cell function

Abstract

Insulin-releasing effects of straight and branched chain 2-keto acids were assessed using clonal glucose-responsive β-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 β-cells depolarised with high KCl and glucose. Voltage-dependent Ca 2+ channel blockade, with verapamil, or depletion of extracellular Ca 2+ 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 β-cell function at least partially independently of K +-ATP channel activity, both through their mitochondrial metabolism and regulation of Ca 2+ influx.