Abstract
Leucine and monomethyl succinate initiate insulin release, and glutamine potentiates leucine-induced insulin release. Alanine enhances and malate inhibits leucine plus glutamine-induced insulin release. The insulinotropic effect of leucine is at least in part secondary to its ability to activate glutamate oxidation by glutamate dehydrogenase (Sener, A., Malaisse-Lagae, F., and Malaisse, W. J. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 5460-5464). The effect of these other amino acids or Krebs cycle intermediates on insulin release also correlates with their effects on glutamate dehydrogenase and their ability to regulate inhibition of this enzyme by alpha-ketoglutarate. For example, glutamine enhances insulin release and islet glutamate dehydrogenase activity only in the presence of leucine. This could be because leucine, especially in the presence of alpha-ketoglutarate, increases the Km of glutamate and converts alpha-ketoglutarate from a noncompetitive to a competitive inhibitor of glutamate. Thus, in the presence of leucine, this enzyme is more responsive to high levels of glutamate and less responsive to inhibition by alpha-ketoglutarate. Malate could decrease and alanine could increase insulin release because malate increases the generation of alpha-ketoglutarate in islet mitochondria via the combined malate dehydrogenase-aspartate aminotransferase reaction, and alanine could decrease the level of alpha-ketoglutarate via the alanine transaminase reaction. Monomethyl succinate alone is as stimulatory of insulin release as leucine alone, and glutamine enhances the action of both. Succinyl coenzyme A, leucine, and GTP are all bound in the same region on glutamate dehydrogenase, where GTP is a potent inhibitor and succinyl coenzyme A and leucine are comparable activators. Thus, the insulinotropic properties of monomethyl succinate could result from it increasing the level of succinyl coenzyme A and decreasing the level of GTP via the succinate thiokinase reaction.
Highlights
Leucine and monomethyl succinate initiate insulin sulin release from pancreatic islets (1-3)
Leucine is the most release, and glutamine potentiatesleucine-induced in- potent amino acid in promoting insulin release both in vivo sulin release
Glutamine enhances insulin release and islet glutamate dehydrogenase activity only in thepresence of leucine. This could be because leucine, especially in the presence of a-ketoglutarate, increases thKe,of glutamate and converts a-ketoglutarate froamnoncompetitive to and in vitro (1-7) and in activating islet glutamate dehydrogenase (1,3, 8). part of the effects of leucine on insulin release are probably related to its metabolism (6), the nonmetabolized analog of leucine, 2-aminobicyclo(2.2.1)heptane carboxylic acid (BCH)’ is almost as effective as leucine in stimulating insulin release and the reaction between endogenous glutamate and glutamatedehydrogenase (1-3,6, 7)
Summary
Glutamine enhances insulin release and islet glutamate dehydrogenase activity only in thepresence of leucine. The insulinotropic properties of monomethyl succinate could result from it increasing the level of a-ketoglutarate via the mitochondrial alanine aminotransferase reaction (14), should increase insulin release. Inhibiting succinate dehydrogenase with malonate decreases a-ketoglutarate generation which enhances glutamate deamination (10). Could enhance glutamate deamination (Scheme I) and insulin release because succinate could increase the mitochondrial level of succinyl-CoA (a glutamate dehydrogenase activator). There is a 1:l correlation between the ability of an amino acid to function as an activator of glutamate oxidation by glutamate dehydrogenase (L-glutamate:NAD(P) oxidoreductase deaminating, EC 1.4.1.3) and its ability to promote inand decrease the level of GTP (apotent glutamate dehydrogenase inhibitor) via the succinate thiokinase reaction.’.
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