Selective Inhibition of N -Methyl- D -aspartate Receptors with GluN2B Subunit Protects b Cells against Stress-Induced Apoptotic Cell Death S

Participation of N -methyl- D -aspartate (NMDA) receptors (NMDARs) in the failure of pancreatic b cells during development of type 2 diabetes mellitus is discussed. Our study inves- tigates whether b cell mass and function can be preserved by selectively addressing the GluN2B subunit of the NMDAR. NMDAR activation by NMDA and its coagonist glycine moder-ately influenced electrical activity and Ca 2 1 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 m M) 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

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