The glutamate signalling in islet of Langerhans: molecular mechanisms of modulation

Increasing evidence suggests that the excitatory neurotransmitter L-glutamate functions as a modulator in the islet of Langerhans, an endocrine organ involved in blood glucose homeostasis. It is release by α-cells and, by acting on specific receptors, it modulates hormone secretion and β-cell mass. Its extracellular concentration is mainly controlled by the glutamate transporter GLT1 which is expressed on the plasma membrane of β-cells (Di Cairano et al, JBC 2011; 286: 14007). Aim of the proposed research was to verify the impact of acute and chronic changes in glucose concentrations on GLT1 localization/function and glutamate signalling in the islet. We found that acute exposure of human and clonal β-cells to high glucose concentrations (15 mM glucose) inhibited the GLT1 transport activity measured by [3H]D-glutamate uptake, in a dose-dependent manner. Furthermore, total internal reflection microscopy experiments performed on β-cells transfected with a GFP-GLT1 tagged transporter demonstrated that glucose stimulation decreased the surface stability of GLT1 and increased its endocytosis. Chronic exposure of human and clonal β-cells to high glucose concentrations caused the GLT1 relocalization in degradative compartments and significantly reduced its total expression. Interestingly, a similar intracellular GLT1 staining was detected in human islets from type 2 diabetic donors (n=8) but not from healthy controls (n=5). Understanding the molecular mechanisms that control glutamate release and signalling in islet of Langerhans may be important to control glucose homeostasis in health and disease.