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(1). In the consensus model of glucose-stimulated insulin secretion, ATP is generated by mitochondrial metabolism, promoting closure of ATP-sensitive potassium (K-ATP) channels, which depolarizes the plasma membrane(2,3). Subsequently, opening of voltage-sensitive Ca2+ channels increases the cytosolic Ca2+ concentration ([Ca2+](c)) which constitutes the main trigger initiating insulin exocytosis(1,3.4), Nevertheless, the Ca2+ signal alone is not sufficient for sustained secretion. Furthermore, glucose elicits a secretory response under conditions of damped, elevated [Ca2+](c) (refs 5, 6), A mitochondrial messenger must therefore exist which is distinct from ATP(7,8). We have 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.