The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Abstract

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 at 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 ␣-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal ␤-cell lines and human islet ␤-cells but not in ␣-cells. In human islets, glutamate-induced ␤-cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of ␤-cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced ␤-cell death, whereas GLT1 up-regulation promoted ␤-cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that ␤-cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.

Differential Expression of the Glutamate Transporter GLT-1 in Pancreas

“…This raises the interesting possibility that glutamate transporter expression in the pancreas could help terminate cycles of glucagon release that are potentiated by extracellular glutamate. In addition, there is new evidence that glutamate induces oxidative stress in islets (Di Cairano et al 2011). Whether GLT-1 protects against oxidative stress by protecting cells in the pancreas against the potentially toxic properties of glutamate (Di Cairano et al 2011) and/or ammonia (Chan and Butterworth 1999;Butterworth 2002) requires further study.…”

GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets

“…This loss has been attributed to the lack of intracellular regulation of beta-to alpha-cell signaling during hypoglycemia [124] and may account for the elevated plasma glucagon levels in diabetes patients, indicating alpha-cell hypersecretion [125,126]. As observed for neurons, beta cells are sensitive to elevated extracellular glutamate levels and show signs of secretory defects and apoptosis at high glutamate levels [122]. This effect was not prevented by AMPA-R and Kainate-R antagonists and therefore unlikely caused by excitotoxicity.…”

“…As outlined in detail in the CNS portion of this chapter, the glutamate/cystine antiporter system xc(À) exchanges intracellular glutamate for extracellular cystine. Excess extracellular glutamate inhibits and/or reverts the activity of the antiporter, thus depleting the cells of cysteine, a building block of the antioxidant glutathione, possibly increasing the cells' vulnerability to oxidative stress [122]. Upregulation of EAAT1 expression on beta cells protects beta cells from glutamate-induced toxicity [122], indicating glutamate signaling as a potential therapeutic target.…”

“…Excess extracellular glutamate inhibits and/or reverts the activity of the antiporter, thus depleting the cells of cysteine, a building block of the antioxidant glutathione, possibly increasing the cells' vulnerability to oxidative stress [122]. Upregulation of EAAT1 expression on beta cells protects beta cells from glutamate-induced toxicity [122], indicating glutamate signaling as a potential therapeutic target. Notably, many effective antidiabetic drugs such as GLP-1, exenatide, and glitazones also show significant neuroprotective activity against glutamate-induced cytotoxicity in the brain [127,128].…”

“…As islets are depolarized by external glucose, the NMDA-R-mediated repolarization of the beta cells is a negative feedback regulation of glucose-stimulated insulin secretion. Extracellular glutamate is taken up by EAAT1 and 2 expressed on alpha cells [122].…”