Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis.
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.
Maechler
P
P
Department of Internal Medicine, University Medical Centre, Geneva, Switzerland. pierre.maechler@medecine.unige.ch
Wollheim
C B
CB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D007328:Insulin; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D005947:Glucose