Glucose and non-glucidic nutrients exert permissive effects on 2-keto acidregulation of pancreatic beta-cell function

Insulin-releasing effects of straight and branched chain 2-keto acids were assessed using clonal glucose-responsive beta-cells. Pyruvic acid (PA), 2-k etovaleric 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 stimul atory 2-keto acids also promoted the stimulatory activity of D-glyceraldehy de, L-leucine or L-arginine. Responses to PAI KV, KIV or KMV were significa ntly reduced by transport inhibition with 2-cyano-3 hydroxycinnamate, gluco kinase inhibition with mannoheptulose or metabolic inhibition with sodium a zide or sodium cyanide. Membrane hyperpolarisation with K+ depletion or dia zoxide 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 KCI and glucose. Voltage-dependent Ca2+ c hannel blockade, with verapamil, or depletion of extracellular Ca2+ abolish ed the secretory activity of 2-keto acids. Collectively, these results indi cate that glucose and metabolisable nutrients exert permissive effects on 2 -keto acid-induced insulin release. In addition, KV. KIV and KMV can regula te beta-cell function at least partially independently of K+-ATP channel ac tivity, both through their mitochondrial metabolism and regulation of Ca2influx. (C) 1999 Elsevier Science B.V. All rights reserved.