Glutamate is not a messenger in insulin secretion

Experiments do not support a recent claim that glutamate formed from the am ination of citric acid cycle-derived alpha -ketoglutarate is a messenger in glucose-induced insulin secretion (Maechler, P., and Wollheim, C. (1999) N ature 402, 685-689), Glucose, leucine, succinic acid methyl ester, and alph a -ketoisocaproic acid all markedly stimulate insulin release but do not in crease 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 gl utamine, is applied to islets, insulin release is almost as high as with gl ucose alone. This is consistent with the known ability of leucine to allost erically activate glutamate deamination by glutamate dehydrogenase, which c an supply alpha -ketoglutarate to the citric acid cycle. Experiments with m itochondria from pancreatic islets suggest that flux through the glutamate dehydrogenase reaction is quiescent during glucose-induced insulin secretio n. These experiments support the traditional idea that when insulin release is associated with flux through glutamate dehydrogenase, the flux is in th e direction of alpha -ketoglutarate.