Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

Jan Marquard, Silke Otter, Alena Welters, Alin Stirban, Annelie Fischer, Jan Eglinger, Diran Herebian, Olaf Kletke, Maša Skelin Klemen, Andraž Stožer, Stephan Wnendt, Lorenzo Piemonti, Martin Köhler, Jorge Ferrer, Bernard Thorens, Freimut Schliess, Marjan Slak Rupnik, Tim Heise, Per-olof Berggren, Nikolaj KlöckerThomas Meissner, Ertan Mayatepek, Daniel Eberhard, Martin Kragl, Eckhard Lammert

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca2+ concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.
Original languageEnglish
Pages (from-to)363-372
Number of pages10
JournalNature Medicine
Volume21
Issue number4
Early online date16 Mar 2015
DOIs
Publication statusPublished - 30 Apr 2015

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    Marquard, J., Otter, S., Welters, A., Stirban, A., Fischer, A., Eglinger, J., Herebian, D., Kletke, O., Klemen, M. S., Stožer, A., Wnendt, S., Piemonti, L., Köhler, M., Ferrer, J., Thorens, B., Schliess, F., Rupnik, M. S., Heise, T., Berggren, P., ... Lammert, E. (2015). Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nature Medicine, 21(4), 363-372. https://doi.org/10.1038/nm.3822