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 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 -