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 Klöcker; Thomas Meissner; Ertan Mayatepek; Daniel Eberhard; Martin Kragl; Eckhard Lammert

doi:10.1038/nm.3822

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 journal › Article › peer-review

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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 language	English
Pages (from-to)	363-372
Number of pages	10
Journal	Nature Medicine
Volume	21
Issue number	4
Early online date	16 Mar 2015
DOIs	https://doi.org/10.1038/nm.3822
Publication status	Published (in print/issue) - 30 Apr 2015

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10.1038/nm.3822

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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

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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 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.",

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, {Ma{\v s}a Skelin} and Andra{\v z} Sto{\v z}er and Stephan Wnendt and Lorenzo Piemonti and Martin K{\"o}hler and Jorge Ferrer and Bernard Thorens and Freimut Schliess and Rupnik, {Marjan Slak} and Tim Heise and Per-olof Berggren and Nikolaj Kl{\"o}cker and Thomas Meissner and Ertan Mayatepek and Daniel Eberhard and Martin Kragl and Eckhard Lammert",

year = "2015",

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doi = "10.1038/nm.3822",

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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, MS, Heise, T, Berggren, P, 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

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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 Slak

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 - 2015/4/30

Y1 - 2015/4/30

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 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.

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 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.

UR - http://www.nature.com/articles/nm.3822

UR - https://pure.ulster.ac.uk/en/publications/characterization-of-pancreatic-nmda-receptors-as-possible-drug-ta

U2 - 10.1038/nm.3822

DO - 10.1038/nm.3822

M3 - Article

SN - 1078-8956

VL - 21

SP - 363

EP - 372

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

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

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