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Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis.
Pancreatic endocrine cells employ a sophisticated system of paracrine and autocrine signals to synchronize their activities, including glutamate which controls hormone release and β-cell viability by acting on glutamate receptors expressed by endocrine cells. We here investigate whether alteration of the Excitatory Amino Acid Transporter 2 (EAAT2), the major glutamate clearance system in the islet, may occur in type 2 diabetes mellitus (T2DM) and contribute to β-cell dysfunction. Increased EAAT2 intracellular localization was evident in islets of Langerhans from T2DM subjects as compared with healthy control subjects, despite similar expression levels. Chronic treatment of islets from healthy donors with high glucose concentrations led to the transporter internalization in vesicular compartments and reduced [H3 ]-D-glutamate uptake (65±5% inhibition), phenocopying the findings in T2DM pancreatic sections. The transporter relocalization was associated to decreased Akt phosphorylation protein levels, suggesting an involvement of the PI3K/Akt pathway in the process. In line with this, PI3K inhibition by 100 µM LY294002 treatment in human and clonal β-cells, caused the transporter relocalization in intracellular compartments and significantly reduced the glutamate uptake compared to control conditions, suggesting that hyperglycemia changes the trafficking of the transporter to the plasma membrane. Upregulation of the glutamate transporter upon treatment with the antibiotic ceftriaxone rescued hyperglycemia-induced β-cells dysfunction and death. Our data underscore the significance of EAAT2 in regulating islet physiology and provide a rationale for potential therapeutic targeting of this transporter to preserve β-cell survival and function in diabetes.
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