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

被引：132

作者：

Marquard, Jan ^{[1
,2
]}

Otter, Silke ^{[1
,3
,4
]}

Welters, Alena ^{[1
,2
,3
,4
]}

Stirban, Alin ^{[5
]}

Fischer, Annelie ^{[5
]}

Eglinger, Jan ^{[1
,3
,4
]}

Herebian, Diran ^{[2
]}

Kletke, Olaf ^{[6
]}

Klemen, Masa Skelin ^{[7
]}

Stozer, Andraz ^{[7
,8
]}

Wnendt, Stephan ^{[9
]}

Piemonti, Lorenzo ^{[10
]}

Kohler, Martin ^{[11
]}

Ferrer, Jorge ^{[12
,13
]}

Thorens, Bernard ^{[14
]}

Schliess, Freimut ^{[5
]}

Rupnik, Marjan Slak ^{[7
,8
,15
]}

Heise, Tim ^{[5
]}

Berggren, Per-Olof ^{[11
]}

Kloecker, Nikolaj ^{[6
]}

Meissner, Thomas ^{[2
]}

Mayatepek, Ertan ^{[2
]}

Eberhard, Daniel ^{[1
]}

Kragl, Martin ^{[1
,4
]}

Lammert, Eckhard ^{[1
,3
,4
]}

机构：

[1] Univ Dusseldorf, Inst Metab Physiol, Dusseldorf, Germany

[2] Univ Childrens Hosp Dusseldorf, Dept Gen Pediat Neonatol & Pediat Cardiol, Dusseldorf, Germany

[3] German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Beta Cell Biol, Dusseldorf, Germany

[4] German Ctr Diabet Res, Partner Dusseldorf, Dusseldorf, Germany

[5] Profil Inst Metab Res, Neuss, Germany

[6] Univ Hosp Dusseldorf, Inst Neuro & Sensory Physiol, Dusseldorf, Germany

[7] Univ Maribor, Fac Med, Inst Physiol, SLO-2000 Maribor, Slovenia

[8] Univ Maribor, Ctr Open Innovat & Res, SLO-2000 Maribor, Slovenia

[9] MLM Med Labs GmbH, Monchengladbach, Germany

[10] Ist Sci San Raffaele, Ist Ricovero & Cura Carattere Sci, Diabet Res Inst, I-20132 Milan, Italy

[11] Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, Stockholm, Sweden

[12] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England

[13] Ctr Invest Biomed Red Diabet & Enfermedades Metab, Inst Invest Biomed August Pi i Sunyer, Genom Programming Beta Cells Lab, Barcelona, Spain

[14] Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland

[15] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Physiol, Vienna, Austria

来源：

NATURE MEDICINE | 2015年 / 21卷 / 04期

基金：

瑞典研究理事会; 英国惠康基金;

关键词：

IONOTROPIC GLUTAMATE RECEPTORS; INSULIN-SECRETION; BETA-CELL; GLUCOSE-TOLERANCE; CYTOPLASMIC CA2+; INHIBITION; CHANNELS; DEXTROMETHORPHAN; GLUCAGON; RELEASE;

D O I：

10.1038/nm.3822

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：363 / +

页数：14

共 70 条

[1] Hypoglycaemia in Type 2 diabetes [J].