NMDAR antagonists for the treatment of diabetes mellitus-Current status and future directions

Diabetes mellitus is characterized by chronically elevated blood glucose levels accelerated by a progressive decline of insulin‐producing β‐cells in the pancreatic islets. Although medications are available to transiently adjust blood glucose to normal levels, the effects of current drugs are limited when it comes to preservation of a critical mass of functional β‐cells to sustainably maintain normoglycemia. In this review, we recapitulate recent evidence on the role of pancreatic N‐methyl‐D‐aspartate receptors (NMDARs) in β‐cell physiology, and summarize effects of morphinan‐based NMDAR antagonists that are beneficial for insulin secretion, glucose tolerance and islet cell survival. We further discuss NMDAR‐mediated molecular pathways relevant for neuronal cell survival, which may also be important for the preservation of β‐cell function and mass. Finally, we summarize the literature for evidence on the role of NMDARs in the development of diabetic long‐term complications, and highlight beneficial pharmacologic aspects of NMDAR antagonists in diabetic nephropathy, retinopathy as well as neuropathy