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 S lak Rupnik, Tim Heise, Per Olof Berggren, Nikolaj KlöckerThomas Meissner, Ertan Mayatepek, Daniel Eberhard, Martin Kragl, Eckhard Lammert

Research output: Contribution to journalArticle

72 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 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.

Original languageEnglish (US)
Pages (from-to)363-372
Number of pages10
JournalNature Medicine
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Fingerprint

N-Methyl-D-Aspartate Receptors
Dextromethorphan
Glucose
Islets of Langerhans
Pharmaceutical Preparations
Insulin
Type 2 Diabetes Mellitus
Dextrorphan
Insulin-Secreting Cells
Synaptic Transmission
Nervous System
Blood Glucose
Diabetes Mellitus
Clinical Trials
Neurons
Serum

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Marquard, J., Otter, S., Welters, A., Stirban, A., Fischer, A., Eglinger, J., ... 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

Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. / Marquard, Jan; Otter, Silke; Welters, Alena; Stirban, Alin; Fischer, Annelie; Eglinger, Jan; Herebian, Diran; Kletke, Olaf; Klemen, Maša Skelin; Stožer, Andraž; Wnendt, Stephan; Piemonti, Lorenzo; Köhler, Martin; Ferrer, Jorge; Thorens, Bernard; Schliess, Freimut; Rupnik, Marjan S lak; Heise, Tim; Berggren, Per Olof; Klöcker, Nikolaj; Meissner, Thomas; Mayatepek, Ertan; Eberhard, Daniel; Kragl, Martin; Lammert, Eckhard.

In: Nature Medicine, Vol. 21, No. 4, 01.04.2015, p. 363-372.

Research output: Contribution to journalArticle

Marquard, J, Otter, S, Welters, A, Stirban, A, Fischer, A, Eglinger, J, Herebian, D, Kletke, O, Klemen, MS, Stožer, A, Wnendt, S, Piemonti, L, Köhler, M, Ferrer, J, Thorens, B, Schliess, F, Rupnik, MSL, Heise, T, Berggren, PO, Klöcker, N, Meissner, T, Mayatepek, E, Eberhard, D, Kragl, M & Lammert, E 2015, 'Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment', Nature Medicine, vol. 21, no. 4, pp. 363-372. https://doi.org/10.1038/nm.3822
Marquard J, Otter S, Welters A, Stirban A, Fischer A, Eglinger J et al. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nature Medicine. 2015 Apr 1;21(4):363-372. https://doi.org/10.1038/nm.3822
Marquard, Jan ; Otter, Silke ; Welters, Alena ; Stirban, Alin ; Fischer, Annelie ; Eglinger, Jan ; Herebian, Diran ; Kletke, Olaf ; Klemen, Maša Skelin ; Stožer, Andraž ; Wnendt, Stephan ; Piemonti, Lorenzo ; Köhler, Martin ; Ferrer, Jorge ; Thorens, Bernard ; Schliess, Freimut ; Rupnik, Marjan S lak ; Heise, Tim ; Berggren, Per Olof ; Klöcker, Nikolaj ; Meissner, Thomas ; Mayatepek, Ertan ; Eberhard, Daniel ; Kragl, Martin ; Lammert, Eckhard. / Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. In: Nature Medicine. 2015 ; Vol. 21, No. 4. pp. 363-372.
@article{820408c002db4e959d1b7a25c5b63efd,
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.",
author = "Jan Marquard and Silke Otter and Alena Welters and Alin Stirban and Annelie Fischer and Jan Eglinger and Diran Herebian and Olaf Kletke and Klemen, {Maša Skelin} and Andraž Stožer and Stephan Wnendt and Lorenzo Piemonti and Martin K{\"o}hler and Jorge Ferrer and Bernard Thorens and Freimut Schliess and Rupnik, {Marjan S lak} and Tim Heise and Berggren, {Per Olof} and Nikolaj Kl{\"o}cker and Thomas Meissner and Ertan Mayatepek and Daniel Eberhard and Martin Kragl and Eckhard Lammert",
year = "2015",
month = "4",
day = "1",
doi = "10.1038/nm.3822",
language = "English (US)",
volume = "21",
pages = "363--372",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

AU - Marquard, Jan

AU - Otter, Silke

AU - Welters, Alena

AU - Stirban, Alin

AU - Fischer, Annelie

AU - Eglinger, Jan

AU - Herebian, Diran

AU - Kletke, Olaf

AU - Klemen, Maša Skelin

AU - Stožer, Andraž

AU - Wnendt, Stephan

AU - Piemonti, Lorenzo

AU - Köhler, Martin

AU - Ferrer, Jorge

AU - Thorens, Bernard

AU - Schliess, Freimut

AU - Rupnik, Marjan S lak

AU - Heise, Tim

AU - Berggren, Per Olof

AU - Klöcker, Nikolaj

AU - Meissner, Thomas

AU - Mayatepek, Ertan

AU - Eberhard, Daniel

AU - Kragl, Martin

AU - Lammert, Eckhard

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84926685729&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926685729&partnerID=8YFLogxK

U2 - 10.1038/nm.3822

DO - 10.1038/nm.3822

M3 - Article

C2 - 25774850

AN - SCOPUS:84926685729

VL - 21

SP - 363

EP - 372

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 4

ER -