A growing body of evidence suggests that extracellular glutamate, the major excitatory neurotransmitter in the central nervous system, acts as a signaling molecule in the endocrine pancreas and control hormon secretions, but whether it also exerts a toxic effect on endocrine cells is unknown. Aim of this study was to investigate the vulnerability of beta-cells to extracellular glutamate, and to verify the expression and function of a glutamate clearance system in pancreatic islet cells.

We show that chronic exposure to elevate glutamate concentrations exerts a toxic effect on pancreatic beta-cells. The glutamate toxicity was mediated by ionotropic glutamate receptors' activation and increased intracellular oxidative stress. Moreover, we provide evidence that the key regulator of the extracellular glutamate concentration in the islet is the excitatory amino acid transporter 2 (EAAT2). EAAT2 selectively localizes on beta-cell membranes and its down regulation by pharmacological blockade or by small harping RNA causes beta-cell death.

Our data demonstrate that glutamate toxicity is a novel cause of beta-cell death and identify the Na-dependent glutamate transporter EAAT2 as a key regulator of glutamate homeostasis and beta-cell survival in islet of Langerhans.