ESPE Abstracts (2014) 82 FC3.5

Pancreatic N-Methyl-D-Aspartate Receptors as Novel Drug Targets for The Treatment of Diabetes Mellitus

Alena Weltersa,b, Jan Marquarda,b, Silke Otterb,c, Alin Stirbane, Jan Eglingerb,c, Diran Herebiana, Andraz Stozerg, Stephan Wnendth, Lorenzo Piemontii, Martin Köhlerj, Freimut Schliesse, Marjan Slak Rupnikg, Tim Heisee, Per-Olof Berggrenj, Nikolaj Klöckerf, Ertan Mayatepeka, Daniel Eberhardb, Martin Kraglb,d, Eckhard Lammertb,c & Thomas Meissnera

aDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Düsseldorf, Germany; bInstitute of Metabolic Physiology, Heinrich-Heine University, Düsseldorf, Germany; cInstitute for Beta Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research, Düsseldorf, Germany; dGerman Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, Neuherberg, Germany; eProfil Institute for Clinical Research, Neuss, Germany; fInstitute of Neuro- and Sensory Physiology, University Hospital Düsseldorf, Düsseldorf, Germany; gInstitute of Physiology, Medical Faculty, Centre for Open Innovations and Research, University of Maribor, Maribor, Slovenia; hMLM Medical Labs GmbH, Mönchengladbach, Germany; iDiabetes Research Institute (DRI), San Raffaele Scientific Institute, Milan, Italy; jThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden

Background: N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that are widely expressed in the CNS where they play an important role in neurotransmission and cell viability and serve as drug targets for the treatment of neurodegenerative disorders.

Objective and hypotheses: Much less is known about the role of pancreatic NMDARs. Since neurons and pancreatic islets have many features in common, we hypothesized that drugs acting on the CNS might also act on pancreatic β cells and may be useful for the treatment of insulin secretion disorders.

Method: We used a genetic and pharmacologic approach to inhibit NMDA receptors in rat insulinoma cells, mouse and human pancreatic islets and pancreas of mice to elucidate the role of pancreatic NMDARs in insulin secretion, glucose tolerance and calcium oscillations. We further studied the effect of the NMDAR antagonist dextromethorphan (DXM) on glucose tolerance, islet insulin content and β cell mass in a type two diabetes mouse model. Finally, we conducted a phase IIa clinical trial in type 2 diabetic patients.

Results: Here, we demonstrate for the first time that antagonizing pancreatic NMDARs, either genetically or pharmacologically with the over-the-counter drug DXM, selectively increases glucose-stimulated insulin secretion (GSIS) from rat insulinoma cells, mouse and human pancreatic islets and improves glucose tolerance in mice without affecting basal insulin release. We further show that long-term treatment with DXM delays the onset of overt type 2 diabetes and increases islet insulin content and β cell mass in a relevant type 2 diabetic mouse model (db/db). Finally, in a phase IIa clinical trial DXM selectively increased postprandial plasma insulin concentrations and improved glucose tolerance in type 2 diabetic patients.

Conclusion: In summary, our data reveal a regulatory role of NMDARs in pancreatic islets and proposes NMDARs as novel drug targets for diabetes treatment.

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