The glutamate transporter GLT1/EAAT2 in islet of Langerhans : a key player in the control of β-cell function and integrity in health and disease

Glutamate, the major excitatory neurotransmitter in the central nervous system, is an important signalling molecule in islets of Langerhans. Our previous work demonstrates that glutamate homeostasis is critical to control hormone release and β-cell integrity and that the glutamate transporter GLT1/EAAT2, by controlling the extracellular glutamate level, plays a key role in these processes (1). Aim of the proposed research was to verify whether the GLT1 localization and function may be altered in Diabetes Mellitus. We found that exposure of human and clonal β-cells to elevated glucose concentrations (16.7 mM glucose) did not significantly affect the total GLT1 expression (95±4% of 5.5mM glucose) but caused its relocalization in intracellular compartments. Accordingly, GLT1 transport activity measured by [3H]D-glutamate uptake was inhibited by 25±5% as compared to 5.5mM glucose (P<0.01). Total internal reflection microscopy experiments demonstrated that glucose treatments decreased the surface stability of GLT1 and increased its endocytosis. A similar relocalization was observed in the presence of LY294 an inhibitor of PI3K, a kinase severely downregulated in hyperglicemic conditions and diabetes (2). These results indicate that GLT1 dysfunction is an early event in diabetes mellitus pathogenesis. Understanding the factors and the molecular mechanism that control GLT1 in islet of Langerhans may be important to control β-cell function and integrity in health and disease. 1. Di Cairano et al, JBC 2011; 286: 14007 2. Folli et al, PlosOne, 2011; 6:e28050