2. Academic Validation
  3. Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis

Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis

  • Am J Physiol Endocrinol Metab. 2024 May 1. doi: 10.1152/ajpendo.00069.2024.
Alessandra Galli 1,  Stefania Moretti 1,  Nevia Dule 1,  Eliana Sara Di Cairano 1,  Michela Castagna 2,  Paola Marciani 3,  Cristina Battaglia 4,  Federico Bertuzzi 5,  Ida Pastore 6,  Paolo Fiorina 7,  Stefano La Rosa 8,  Alberto Davalli 9,  Franco Folli 10,  Carla Perego 11
Affiliations

Affiliations

  • 1 Pharmacological and Biomolecular Sciences, University of Milan, Italy.
  • 2 Molecular Sciences Applied to Biosystems, University of Milan.
  • 3 Institute of General Physiology and Biochemistry, University of Milan, Milan, Italy.
  • 4 Medical Biotechnology and Translational Medicine, University of Milan, Italy.
  • 5 Azienda Ospedaliera Niguarda Ca' Granda - Unità di diabetologia.
  • 6 Endocrinology Unit, ASST Fatebenefratelli-Sacco, Italy.
  • 7 International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC; Nephrology Division, Boston Children's Hospital, Harvard Medical School; Division of Endocrinology, University of Milan, Milan, Italy.
  • 8 Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Italy.
  • 9 IRCCS Ospedale San Raffaele, Italy.
  • 10 University of Milan, Milano, Italy.
  • 11 Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan, Milan, Italy.
PMID: 38690938 DOI: 10.1152/ajpendo.00069.2024
Abstract

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.

Keywords

EAAT2/GLT1; PI3K; glutamate; islets of Langerhans; type 2 diabetes mellitus.

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