The glial glutanmate transporter 1 (GLT1) controls glutamate homeostasis and preserves beta-cell integrity in islet of Langerhans

Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained under physiological concentrations by high affinity glutamate transporters of the SoLute Carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans, where it is secreted by the alpha-cells together with glucagon and acts as signalling molecule to modulate hormone secretion. Nevertheless, our knowledge regarding the effects of glutamate on islet cells\u2019 physiology is still incomplete. The aim of this work was to investigate whether glutamate also affect islet cells viability and hormone secretion. We demonstrated that chronic exposure to glutamate exerted a cytotoxic effect in clonal beta-cell lines and human islet beta-cells but not in alpha-cells. In human islets, glutamate-induced beta-cell cytotoxicity was associated to increased oxidative stress and led to apoptosis and autophagy. We also provided evidence that the key regulator of extracellular islet glutamate concentration was the glial glutamate transporter 1 (GLT1). GLT1 localized to the plasma membrane of beta-cells, modulated hormone secretion and prevented glutamate-induced cytotoxicity, as shown by the fact that its down-regulation induced beta-cell death while GLT1 up-regulation promoted beta-cell survival. In conclusion, glutamate homeostasis is critical to preserve islet cell signalling and beta-cell integrity and GLT1, by controlling extracellular glutamate levels, may play an important role in the pathogenesis of beta-cell and islet remodelling in diabetes