title: Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment.
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.
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Marquard
authors.affiliation: 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.
authors.forename: Silke
authors.initials: S
authors.lastname: Otter
authors.affiliation: 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.
authors.forename: Alena
authors.initials: A
authors.lastname: Welters
authors.affiliation: Profil Institute for Metabolic Research, Neuss, Germany.
authors.forename: Alin
authors.initials: A
authors.lastname: Stirban
authors.affiliation: Profil Institute for Metabolic Research, Neuss, Germany.
authors.forename: Annelie
authors.initials: A
authors.lastname: Fischer
authors.affiliation: 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.
authors.forename: Jan
authors.identifier: 0000000172341435
authors.initials: J
authors.lastname: Eglinger
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Diran
authors.initials: D
authors.lastname: Herebian
authors.affiliation: Institute of Neuro- and Sensory Physiology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kletke
authors.affiliation: Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
authors.forename: Maša Skelin
authors.initials: MS
authors.lastname: Klemen
authors.affiliation: 1] Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia. [2] Center for Open Innovations and Research, University of Maribor, Maribor, Slovenia.
authors.forename: Andraž
authors.initials: A
authors.lastname: Stožer
authors.affiliation: MLM Medical Labs GmbH, Mönchengladbach, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wnendt
authors.affiliation: Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Köhler
authors.affiliation: 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.
authors.forename: Jorge
authors.identifier: 0000000259595729
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.affiliation: Profil Institute for Metabolic Research, Neuss, Germany.
authors.forename: Freimut
authors.initials: F
authors.lastname: Schliess
authors.affiliation: 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.
authors.forename: Marjan Slak
authors.initials: MS
authors.lastname: Rupnik
authors.affiliation: Profil Institute for Metabolic Research, Neuss, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Heise
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Institute of Neuro- and Sensory Physiology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meissner
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eberhard
authors.affiliation: 1] Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany. [2] German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kragl
authors.affiliation: 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.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Lammert
mesh_terms: D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D003915:Dextromethorphan / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D000077270:Exenatide; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010179:Pancreas / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014688:Venoms / Q000378:metabolism
chemical_list: C121673:Gprin1 protein, mouse; D007328:Insulin; D009419:Nerve Tissue Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D014688:Venoms; D003915:Dextromethorphan; D000077270:Exenatide; D005947:Glucose; D002118:Calcium