The hormone insulin is stored in secretory granules and released from the pancreatic β-cells by exocytosis1. In the consensus model of glucose-stimulated insulin secretion, ATP is generated by mitochondrial metabolism, promoting closure of ATP-sensitive potassium (KATP) channels, which depolarizes the plasma membrane2,3. Subsequently, opening of voltage-sensitive Ca2+ channels increases the cytosolic Ca2+ concentration ([Ca2+]c) which constitutes the main trigger initiating insulin exocytosis1,3,4. Nevertheless, the Ca2+ signal alone is not sufficient for sustained secretion. Furthermore, glucose elicits a secretory response under conditions of clamped, elevated [Ca2+]c (refs 5, 6). A mitochondrial messenger must therefore exist which is distinct from ATP7,8. We have now identified this as glutamate. We show that glucose generates glutamate from β-cell mitochondria. A membrane-permeant glutamate analogue sensitizes the glucose-evoked secretory response, acting downstream of mitochondrial metabolism. In permeabilized cells, under conditions of fixed [Ca2+]c, added glutamate directly stimulates insulin exocytosis, independently of mitochondrial function. Glutamate uptake by the secretory granules is likely to be involved, as inhibitors of vesicular glutamate transport suppress the glutamate-evoked exocytosis. These results demonstrate that glutamate acts as an intracellular messenger that couples glucose metabolism to insulin secretion.
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We thank C. Bartley and G. Chaffard for technical assistance, J. Lou, J. Oberholzer and P. Morel (Department of Surgery, University Hospital of Geneva) for supplying human islets, A. Valeva (Institute of Medical Microbiology, University of Mainz) for α-toxin and T. Pozzan, P. Antinozzi and H. Ishihara for discussions. This study was supported by the Swiss National Science Foundation and the AETAS Foundation (Geneva).
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Maechler, P., Wollheim, C. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature 402, 685–689 (1999) doi:10.1038/45280
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