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.
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We thank C.B. Wollheim and P. Maechler (University of Geneva) for providing INS1E cells, J. Roeper (Goethe University Frankfurt) and S. Seino (Kobe University) for providing Kir6.2-deficient mice, H. Bading (University of Heidelberg) and his colleagues for providing us with a GluN1-positive control and for helpful discussions, and S. Jakob, B. Bartosinska and A. Leinweber (Heinrich Heine University Düsseldorf) for technical support. We also thank O. Kuß (German Diabetes Center Düsseldorf) and B. Kronhage (Profil Institute for Metabolic Research) for supporting the statistical analyses of the clinical and preclinical data, respectively. P.-O.B. and M. Köhler are supported by the Swedish Research Council and the Family Erling-Persson Foundation. This study was supported by the Heinrich Heine University Düsseldorf; its research training group entitled “In vivo investigations in metabolic pathomechanisms and diseases in Düsseldorf” and its research commission of the medical faculty; the German Center for Diabetes Research; the German Diabetes Center; the Federal Ministry of Health; the Ministry for Innovation, Science and Research of North Rhine–Westphalia; Ipsen Pharma GmbH; and the Anton-Betz Foundation. Research from M.S.K., A. Stožer and M.S.R. was produced within the framework of an operation entitled “Centre of Open Innovation and Research UM (CORE@UM)” (3330-13-500032) and co-funded by the European Regional Development Fund. D.E. and E.L. are supported by the German Research Foundation (La1216/6-1), and M. Kragl and E.L. are supported by the Competence Network Diabetes Mellitus from the Federal Ministry for Education and Research. Human islets were obtained either by L.P. (ECIT consortium, supported by JDRF, Grant Name: Islets for Research; Grant Number: 31-2008-416) or from the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope. A list of all participating IIDP laboratories can be found here: https://iidp.coh.org/center_info.aspx.
J.M., T.M. and E.L. pursue a patent application (WO 2013/029762 A1) entitled Morphinan-derivatives for treating diabetes and related disorders.
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Marquard, J., Otter, S., Welters, A. et al. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21, 363–372 (2015). https://doi.org/10.1038/nm.3822
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