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

Nature. 1999 Dec 9;402(6762):685-9. doi: 10.1038/45280.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Exocytosis*
  • Glucose / metabolism*
  • Glutamic Acid / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Intracellular Membranes / metabolism
  • Islets of Langerhans / metabolism*
  • Membrane Potentials
  • Mitochondria / metabolism*
  • Rats
  • Signal Transduction*
  • Tumor Cells, Cultured


  • Insulin
  • Glutamic Acid
  • Adenosine Triphosphate
  • Glucose