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

• Published in: Nature (London) 1999-12, Vol.402 (6762), p.685-689
• Main Authors: Wollheim, Claes B, Maechler, Pierre
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; ATP; Biological and medical sciences; Cellular biology; Diabetes; Endocrine pancreas; Exocytosis; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Glutamic Acid - metabolism; Hormones. Régulation; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Intracellular Membranes - metabolism; Islets of Langerhans - metabolism; letter; Membrane Potentials; Metabolism; Mitochondria - metabolism; multidisciplinary; Rats; Science; Science (multidisciplinary); Signal Transduction; Studies; Sugar; Tumor Cells, Cultured; Vertebrates: endocrinology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/45280

The hormone insulin is stored in secretory granules and released from the pancreatic β-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 (refs 5, 6). 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 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.