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.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology