Studies on the role of beta-cell metabolism in the insulinotropic effect of alpha-ketoisocaproic acid.
alpha-Ketoisocaproic acid has been shown to be a potent insulin secretagogue but the mechanism has not been elucidated. To define the role of beta-cell metabolism in the insulinotropic activity of alpha-ketoisocaproic acid the utilization of glucose and the oxidation of alpha-ketoisocaproic and isovaleric acid by incubated islets of obese hyperglycemic mice were measured. Glucose metabolism was never enhanced by alpha-ketoisocaproic acid. The same 14CO2 amounts were released from the non-secretagogue [1-14C]isovaleric acid (10 mM) or from alpha-keto[2-14C]isocaproic acid (5--20 mM). Pyruvate (20 mM) did not inhibit alpha-ketoisocaproic acid-induced insulin secretion in spite of reduction of decarboxylation of alpha-ketoisocaproic acid by more than 40%. The results indicate that stimulated insulin release in response to alpha-ketoisocaproic acid is not mediated by an indirect increase in glucose metabolism and further suggest that isovaleryl-CoA and following CoA-esters in alpha-ketoisocaproic acid degradation are not likely recognized as signals. The possibility, however, remains that enhanced intramitochondrial production of reducing equivalents elicits insulin secretion.
D000818:Animals; D002208:Caproates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology*; D051379:Mice; D014631:Valerates / Q000378:metabolism
D002208:Caproates; D007328:Insulin; D007651:Keto Acids; D014631:Valerates; C013082:alpha-ketoisocaproic acid; D005947:Glucose