Volume 1 Supplement 1

Abstracts of the 50th Workshop for Pediatric Research

Open Access

NMDA receptor dependent anti-diabetic effects

  • Jan Marquard1, 2,
  • Silke Otter2, 3, 4,
  • Alena Welters1, 2, 3, 4,
  • Diran Herebian1,
  • Fatih Demir5,
  • Annett Schroeter5,
  • Olaf Kletke5,
  • Martin Kragl2, 3, 4,
  • Daniel Eberhard2, 3, 4,
  • Barbara Bartosinska2, 3, 4,
  • Masa Skelin Klemen6,
  • Andraz Stozer6,
  • Martin Köhler7,
  • Alin Stirban8,
  • Freimut Schliess8,
  • Tim Heise8,
  • Stephan Wnendt9,
  • Marjan Slak Rupnik6,
  • Per-Olof Berggren7,
  • Nikolaj Klöcker5,
  • Thomas Meissner1,
  • Ertan Mayatepek1 and
  • Eckhard Lammert2, 3, 4
Molecular and Cellular Pediatrics20141(Suppl 1):A26

DOI: 10.1186/2194-7791-1-S1-A26

Published: 11 September 2014

Aims

In the central nervous system, NMDA receptors play a pivotal role, however, their role in pancreatic islets has been largely unexplored or is controversial. We hypothesized that NMDA receptors are involved in glucose stimulated insulin secretion from beta cells and might serve as novel drug targets for diabetes treatment.

Methods

We generated mice with a pancreas-specific deletion of all NMDA receptors. The phenotype of these mice and their pancreatic islets were characterized in terms of insulin secretion, glucose tolerance and calcium oscillations. We also pharmacologically inhibited the NMDA receptors in vitro and in vivo. Subsequently, insulin secretion from isolated mouse and human islets as well as blood glucose and plasma insulin concentrations were analyzed in mice and via a clinical trial in type 2 diabetic patients.

Results

Functional NMDA receptors are expressed in insulin producing cells. A pancreas specific NMDA receptor knockout selectively increases glucose stimulated insulin secretion in vitro and improves glucose tolerance in vivo. The pharmacological inhibition of NMDA receptors selectively increases glucose stimulated insulin secretion in vitro and improves glucose tolerance in C57Bl/6 and diabetic mice. In addition, we performed a clinical trial in patients with type 2 diabetes and provided evidence that the NMDA receptor antagonist Dextromethorphan (DXM) lowers blood glucose levels and increases insulin secretion without the risk of hypoglycemia.

Conclusion

We show for the first time that NMDA receptors can be targeted genetically and pharmacologically in mice and men to selectively increase glucose stimulated insulin secretion with improvement of glucose tolerance. We uncovered a new role for NMDA receptors in the pancreas and showed that inhibiting these receptors might serve as a useful treatment of human diabetes in pediatric and adult patients.

Authors’ Affiliations

(1)
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf
(2)
Institute of Metabolic Physiology, Heinrich-Heine University
(3)
Institute for Beta Cell Biology, German Diabetes Center (DDZ)
(4)
German Center for Diabetes Research (DZD e.V.)
(5)
Institute of Neuro- and Sensory Physiology, Heinrich-Heine University
(6)
Institute of Physiology,Faculty of Medicine, University of Maribor
(7)
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet
(8)
Profil Institute for Clinical Research
(9)
MLM Medical Labs GmbH

Copyright

© Marquard et al; licensee Springer 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.