The role of N-methyl-D-aspartate receptors (NMDARs) in pancreatic islet β-cells remains poorly understood. Here, Marquard et al. report that the NMDAR antagonist MK-801 increases glucose-stimulated insulin secretion and improves glucose tolerance in mouse and human islet cells, by extending the depolarization phase in β-cells. Similar effects occurred in isolated islet cells and in mice administered another NMDAR antagonist (the cough suppressant dextromethorphan (DXM)). In diabetic db/db mice, oral DXM administration increased islet insulin content, cell mass and survival, and improved blood glucose control. In a Phase IIa trial in patients with type 2 diabetes, a single oral dose of DXM increased serum insulin concentrations and glucose tolerance.