Role of NMDA Receptors in Pancreatic Islets

Pancreatic islets are cell aggregates that consist of a few dozen to a few thousand endocrine pancreatic cells, primarily β-cells and α-cells. The latter secrete polypeptide hormones into the bloodstream, i.e. insulin and glucagon, to temporally decrease or increase blood glucose, respectively. Therefore, islets are essential for maintaining the concentration of glucose, the key nutrient of the central nervous system. Recently, N-methyl-d-aspartate receptors (NMDARs) were shown to reduce the amount of insulin secreted by β-cells in response to stimulatory glucose concentrations. Likewise, NMDAR deletion in mouse islets increases glucose-induced plasma insulin concentrations and lowers blood glucose. NMDAR expression in β-cells also promotes cell death under inflammatory and diabetogenic conditions. It is hypothesized that NMDARs on β-cells are permanently occupied by glutamate derived from the leaky, fenestrated blood capillary network of the islets, and that NMDAR activity is mainly induced by depolarization of the β-cells. The latter explains why deletion of NMDARs only increases insulin release from β-cells when blood glucose concentrations are high and β-cells are depolarized. Blocking NMDARs with the over-the-counter drug dextromethorphan (DXM) increases insulin release and lowers blood glucose concentrations in mice. In two clinical trials, DXM selectively increases serum insulin concentrations in individuals with type 2 diabetes mellitus and selectively lowers blood glucose whenever the blood glucose concentration is high. Therefore, NMDAR antagonists, and especially DXM, harbor anti-diabetic properties that increase β-cell function and survival.