In the nervous system, excessive activation of
NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of
hyperglycemia. Here we thoroughly investigated whether endogenous
glutamate aggravated β-cell dysfunction under chronic exposure to high-
glucose via activation of NMDARs. The
glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines
after treatment with high-
glucose for 72 h. Decomposing the released
glutamate improved GSIS of β-cells under chronic high-
glucose exposure. Long-term treatment of β-cells with
NMDA inhibited cell viability and decreased GSIS. These effects were eliminated by GluN1 knockout. The NMDAR antagonist
MK-801 or GluN1 knockout prevented high-
glucose-induced dysfunction in β-cells.
MK-801 also decreased the expression of pro-inflammatory
cytokines, and inhibited I-κB degradation, ROS generation and NLRP3
inflammasome expression in β-cells exposed to high-
glucose. Furthermore, another NMDAR antagonist,
Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of
glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by
hyperglycemia.