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

doi:10.1038/nm.3822

. 2015 Apr;21(4):363-72.

doi: 10.1038/nm.3822. Epub 2015 Mar 16.

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

Jan Marquard¹, Silke Otter², Alena Welters³, Alin Stirban⁴, Annelie Fischer⁴, Jan Eglinger², Diran Herebian⁵, Olaf Kletke⁶, Maša Skelin Klemen⁷, Andraž Stožer⁸, Stephan Wnendt⁹, Lorenzo Piemonti¹⁰, Martin Köhler¹¹, Jorge Ferrer¹², Bernard Thorens¹³, Freimut Schliess⁴, Marjan Slak Rupnik¹⁴, Tim Heise⁴, Per-Olof Berggren¹¹, Nikolaj Klöcker⁶, Thomas Meissner⁵, Ertan Mayatepek⁵, Daniel Eberhard¹⁵, Martin Kragl¹⁶, Eckhard Lammert²

Affiliations

¹ 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
² 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] Institute for Beta Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany. [3] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
³ 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany. [3] Institute for Beta Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany. [4] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
⁴ Profil Institute for Metabolic Research, Neuss, Germany.
⁵ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
⁶ Institute of Neuro- and Sensory Physiology, University Hospital Düsseldorf, Düsseldorf, Germany.
⁷ Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
⁸ 1] Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia. [2] Center for Open Innovations and Research, University of Maribor, Maribor, Slovenia.
⁹ MLM Medical Labs GmbH, Mönchengladbach, Germany.
¹⁰ Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milano, Italy.
¹¹ The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
¹² 1] Department of Medicine, Imperial College London, London, UK. [2] Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
¹³ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
¹⁴ 1] Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia. [2] Center for Open Innovations and Research, University of Maribor, Maribor, Slovenia. [3] Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
¹⁵ Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany.
¹⁶ 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.

PMID: 25774850
DOI: 10.1038/nm.3822

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

Jan Marquard et al. Nat Med. 2015 Apr.

. 2015 Apr;21(4):363-72.

doi: 10.1038/nm.3822. Epub 2015 Mar 16.

Authors

Affiliations

¹ 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
² 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] Institute for Beta Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany. [3] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
³ 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany. [3] Institute for Beta Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany. [4] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
⁴ Profil Institute for Metabolic Research, Neuss, Germany.
⁵ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
⁶ Institute of Neuro- and Sensory Physiology, University Hospital Düsseldorf, Düsseldorf, Germany.
⁷ Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
⁸ 1] Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia. [2] Center for Open Innovations and Research, University of Maribor, Maribor, Slovenia.
⁹ MLM Medical Labs GmbH, Mönchengladbach, Germany.
¹⁰ Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milano, Italy.
¹¹ The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
¹² 1] Department of Medicine, Imperial College London, London, UK. [2] Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
¹³ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
¹⁴ 1] Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia. [2] Center for Open Innovations and Research, University of Maribor, Maribor, Slovenia. [3] Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
¹⁵ Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany.
¹⁶ 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.

PMID: 25774850
DOI: 10.1038/nm.3822

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 Ca(2+) 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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Comment in

Diabetes: Dextromethorphan stimulates insulin secretion from pancreatic β cells--a new role for an old drug?
Sargent J. Sargent J. Nat Rev Endocrinol. 2015 May;11(5):253. doi: 10.1038/nrendo.2015.49. Epub 2015 Mar 31. Nat Rev Endocrinol. 2015. PMID: 25824679 No abstract available.
Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs?
Wollheim CB, Maechler P. Wollheim CB, et al. Nat Med. 2015 Apr;21(4):310-1. doi: 10.1038/nm.3835. Nat Med. 2015. PMID: 25849270 No abstract available.

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References

1. N Engl J Med. 2013 Jul 25;369(4):362-72 - PubMed
1. Nat Rev Drug Discov. 2014 Jun;13(6):465-76 - PubMed
1. J Biol Chem. 2014 May 2;289(18):12435-45 - PubMed
1. Nat Neurosci. 2012 Sep;15(9):1272-80 - PubMed
1. Nature. 2014 Jul 10;511(7508):191-7 - PubMed

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[1] N Engl J Med. 2013 Jul 25;369(4):362-72 - PubMed

[2] N Engl J Med. 2013 Jul 25;369(4):362-72 - PubMed

[3] Nat Rev Drug Discov. 2014 Jun;13(6):465-76 - PubMed

[4] Nat Rev Drug Discov. 2014 Jun;13(6):465-76 - PubMed

[5] J Biol Chem. 2014 May 2;289(18):12435-45 - PubMed

[6] J Biol Chem. 2014 May 2;289(18):12435-45 - PubMed

[7] Nat Neurosci. 2012 Sep;15(9):1272-80 - PubMed

[8] Nat Neurosci. 2012 Sep;15(9):1272-80 - PubMed

[9] Nature. 2014 Jul 10;511(7508):191-7 - PubMed

[10] Nature. 2014 Jul 10;511(7508):191-7 - PubMed

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

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

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