Editors' ChoicePharmacology

Can a cough suppressant treat diabetes?

Sci. Signal.  28 Apr 2015:
Vol. 8, Issue 374, pp. ec107
DOI: 10.1126/scisignal.aab4140

The functions of the ionotropic N-methyl-D-aspartate receptor (NMDAR) in non-neuronal tissues are not well-understood. Marquard et al. (see also Wollheim and Maechler) investigated the role of the NMDAR in pancreatic insulin release. Glucose metabolism in pancreatic β cells produces ATP, which closes the KATP potassium channel, leading to depolarization and calcium influx through calcium channels and insulin secretion. Islets from mice with a pancreatic epithelial cell-specific knockout of Grin1, which encodes the NMDAR subunit GluN1, exhibited greater glucose-stimulated insulin secretion (GSIS) than did β cells from control mice. When exposed to the NMDAR inhibitor MK-801, dextromethorphan (DXM, a cough suppressant that blocks NMDARs and affects other targets) or the DXM metabolite dextrorphan (DXO), mouse and human islets and the INS1E rat insulinoma cell line showed enhanced GSIS without changes in basal insulin release. Islets from mice lacking a subunit of the KATP channel did not exhibit MK-801–induced enhancement of GSIS. DXO-treated mice had higher glucose-induced plasma insulin concentrations and better glucose tolerance than control mice, an effect of DXO that was absent in the mice lacking pancreatic Grin1. Mice receiving DXM in drinking water overnight had basal plasma insulin and fasting blood glucose concentrations similar to those of control mice but exhibited significantly higher glucose-induced plasma insulin concentrations and better glucose tolerance. In a mouse model of type 2 diabetes (db/db), DXM treatment lowered fasting blood glucose concentrations, increased the insulin content of islets, and reduced the number of apoptotic islet cells. In a clinical trial with 20 male patients with type 2 diabetes, DXM neither increased fasting serum insulin concentrations nor lowered fasting blood glucose concentrations compared to placebo. However, following oral glucose uptake, the DXM-treated group had increased serum insulin concentrations compared to the placebo group. Thus, NMDAR antagonists could enhance pancreatic β cell function without the side effects of hypoglycemia as seen with some currently used antidiabetic drugs.

J. Marquard, S. Otter, A. Welters, A. Stirban, A. Fischer, J. Eglinger, D. Herebian, O. Kletke, M. S. Klemen, A. Stožer, S. Wnendt, L. Piemonti, M. Köhler, J. Ferrer, B. Thorens, F. Schliess, M. S. Rupnik, T. Heise, P.-O. Berggren, N. Klöcker, T. Meissner, E. Mayatepek, D. Eberhard, M. Kragl, E. Lammert, Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat. Med. 21, 363–372 (2015). [PubMed]

C. B. Wollheim, P. Maechler, Beta cell glutamate receptor antagonists: Novel oral antidiabetic drugs? Nat. Med. 21, 310–311 (2015). [PubMed]