Selective Inhibition of N-Methyl-d-aspartate Receptors with GluN2B Subunit Protects β Cells against Stress-Induced Apoptotic Cell Death.

Abstract

Participation of N-methyl-d-aspartate (NMDA) receptors (NMDARs) in the failure of pancreatic β cells during development of type 2 diabetes mellitus is discussed. Our study investigates whether β cell mass and function can be preserved by selectively addressing the GluN2B subunit of the NMDAR. NMDAR activation by NMDA and its coagonist glycine moderately influenced electrical activity and Ca2+ handling in islet cells at a threshold glucose concentration (4-5 mM) without affecting glucose-mediated insulin secretion. Exposure of islet cells to NMDA/glycine or a glucolipotoxic milieu increased apoptosis by 5% and 8%, respectively. The GluN2B-specific NMDAR antagonist WMS-1410 (0.1 and 1 µM) partly protected against this. In addition, WMS-1410 completely prevented the decrease in insulin secretion of about 32% provoked by a 24-hour-treatment with NMDA/glycine. WMS-1410 eliminated NMDA-induced changes in the oxidation status of the islet cells and elevated the sensitivity of intracellular calcium to 15 mM glucose. By contrast, WMS-1410 did not prevent the decline in glucose-stimulated insulin secretion occurring after glucolipotoxic culture. This lack of effect was due to a decrease in insulin content to 18% that obviously could not be compensated by the preservation of cell mass or the higher percentage of insulin release in relation to insulin content. In conclusion, the negative effects of permanent NMDAR activation were effectively counteracted by WMS-1410 as well as the apoptotic cell death induced by high glucose and lipid concentrations. Modulation of NMDARs containing the GluN2B subunit is suggested to preserve β cell mass during development of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: Addressing NMDA receptors containing the GluN2B subunit in pancreatic islet cells has the potential to protect the β cell mass that progressively declines during the development of type 2 diabetes. Furthermore, this study shows that harmful effects of permanent NMDAR activation can be effectively counteracted by the compound WMS-1410, a selective modulator for NMDARs containing the GluN2B subunit.