Abstract
Experiments do not support a recent claim that glutamate formed from the amination of citric acid cycle-derived alpha-ketoglutarate is a messenger in glucose-induced insulin secretion (Maechler, P., and Wollheim, C. (1999) Nature 402, 685-689). Glucose, leucine, succinic acid methyl ester, and alpha-ketoisocaproic acid all markedly stimulate insulin release but do not increase glutamate levels in pancreatic islets. Increasing the intracellular glutamate levels to 10-fold higher than basal levels by adding glutamine to islets does not stimulate insulin release. When leucine, in addition to glutamine, is applied to islets, insulin release is almost as high as with glucose alone. This is consistent with the known ability of leucine to allosterically activate glutamate deamination by glutamate dehydrogenase, which can supply alpha-ketoglutarate to the citric acid cycle. Experiments with mitochondria from pancreatic islets suggest that flux through the glutamate dehydrogenase reaction is quiescent during glucose-induced insulin secretion. These experiments support the traditional idea that when insulin release is associated with flux through glutamate dehydrogenase, the flux is in the direction of alpha-ketoglutarate.
Highlights
From the ‡Childrens Diabetes Center and ¶Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706
If glutamate is an intracellular messenger in insulin secretion, increasing the beta cell glutamate levels by almost any means should stimulate insulin release as long as there is a source of energy supplied by a metabolizable secretagogue
We found higher basal levels of glutamate (1 to 2.5 mM)1 in pancreatic islets than Maechler and Wollheim (1) observed in stimulated insulinoma cells and pancreatic islet cells, and we did not see glutamate levels rise above background levels in the presence of glucose, the most potent physiologic metabolizable insulin secretagogue (Table I)
Summary
From the ‡Childrens Diabetes Center and ¶Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706. Experiments do not support a recent claim that glutamate formed from the amination of citric acid cyclederived ␣-ketoglutarate is a messenger in glucose-induced insulin secretion In addition to glutamine, is applied to islets, insulin release is almost as high as with glucose alone This is consistent with the known ability of leucine to allosterically activate glutamate deamination by glutamate dehydrogenase, which can supply ␣-ketoglutarate to the citric acid cycle. Experiments with mitochondria from pancreatic islets suggest that flux through the glutamate dehydrogenase reaction is quiescent during glucose-induced insulin secretion. These experiments support the traditional idea that when insulin release is associated with flux through glutamate dehydrogenase, the flux is in the direction of ␣-ketoglutarate. The results of the current study support the traditional theory of insulin secretion involving glutamate, which is that leucine, by allosterically activating glutamate dehydrogenase, can stimulate glutamate deamination to ␣-ketoglutarate, which is further metabolized in the citric acid cycle to stimulate insulin secretion (3–9)
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