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

The hormone insulin is stored in secretory granules and released from the p ancreatic beta-cells by exocytosis(1). In the consensus model of glucose-st imulated insulin secretion, ATP is generated by mitochondrial metabolism, p romoting closure of ATP-sensitive potassium (K-ATP) channels, which depolar izes the plasma membrane(2,3). Subsequently, opening of voltage-sensitive C a2+ channels increases the cytosolic Ca2+ concentration ([Ca2+](c)) which c onstitutes the main trigger initiating insulin exocytosis(1,3.4), Neverthel ess, the Ca2+ signal alone is not sufficient for sustained secretion. Furth ermore, glucose elicits a secretory response under conditions of damped, el evated [Ca2+](c) (refs 5, 6), A mitochondrial messenger must therefore exis t which is distinct from ATP(7,8). We have identified this as glutamate, We show that glucose generates glutamate from beta-cell mitochondria, A membr ane-permeant glutamate analogue sensitizes the glucose-evoked secretory res ponse, acting downstream of mitochondrial metabolism. In permeabilized cell s, under conditions of fixed [Ca2+](c), added glutamate directly stimulates insulin exocytosis, independently of mitochondrial function. Glutamate upt ake by the secretory granules is likely to be involved, as inhibitors of ve sicular glutamate transport suppress the glutamate-evoked exocytosis. These results demonstrate that glutamate acts as an intracellular messenger that couples glucose metabolism to insulin secretion.