INSULINOTROPIC ACTION OF METHYL PYRUVATE - ENZYMATIC AND METABOLIC ASPECTS

The metabolism of methyl pyruvate was compared to that of pyruvate in isolated rat pancreatic islets, Methyl pyruvate was found to be more e fficient than pyruvate in supporting the intramitochondrial conversion of pyruvate metabolites to amino acids, inhibiting D-15-[H-3]glucose utilization, maintaining a high ratio between D-[3,4-C-14]glucose or D -[6-C-14]glucose oxidation and D-[5-H-3]glucose utilization, inhibitin g the intramitochondrial conversion of glucose-derived 2-keto acids to their corresponding amino acids, and augmenting (CO2)-C-14 output fro m islets prelabeled with L-[U-C-14]glutamine, Methyl pyruvate also app arently caused a more marked mitochondrial alkalinization than pyruvat e, as judged from comparisons of pH measurements based on the use of e ither a fluorescein probe or C-14-labeled 5,5-dimethyl-oxazolidine-2,4 -dione. Inversely, pyruvate was more efficient than methyl pyruvate in increasing lactate output and generating L-alanine, These converging findings indicate that, by comparison with exogenous pyruvate, its met hyl ester is preferentially metabolized in the mitochondrial, rather t han cytosolic, domain of islet cells, It is proposed that both the pos itive and the negative components of methyl pyruvate insulinotropic ac tion are linked to changes in the net generation of reducing equivalen ts, ATP and H+. (C) 1996 Academic Press, Inc.