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Scientific article
Letter
Open access
English

Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis

Published inNature, vol. 402, no. 6762, p. 685-689
Publication date1999
Abstract

The hormone insulin is stored in secretory granules and released from the pancreatic beta-cells by exocytosis. 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 membrane. Subsequently, opening of voltage-sensitive Ca2+ channels increases the cytosolic Ca2+ concentration ([Ca2+]c) which constitutes the main trigger initiating insulin exocytosis. Nevertheless, the Ca2+ signal alone is not sufficient for sustained secretion. Furthermore, glucose elicits a secretory response under conditions of clamped, elevated [Ca2+]c. A mitochondrial messenger must therefore exist which is distinct from ATP. We have now identified this as glutamate. We show that glucose generates glutamate from beta-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.

Keywords
  • Adenosine Triphosphate/metabolism
  • Animals
  • Exocytosis
  • Glucose/metabolism
  • Glutamic Acid/metabolism
  • Humans
  • Insulin/secretion
  • Intracellular Membranes/metabolism
  • Islets of Langerhans/secretion
  • Membrane Potentials
  • Mitochondria/metabolism
  • Rats
  • Signal Transduction
  • Tumor Cells, Cultured
Citation (ISO format)
MAECHLER, Pierre, WOLLHEIM, Claes. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. In: Nature, 1999, vol. 402, n° 6762, p. 685–689. doi: 10.1038/45280
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Article (Published version)
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ISSN of the journal0028-0836
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