title: An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes.
abstract: 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.
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Huang
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.|Department of Physiology, Changzhi medical college, Changzhi, Shanxi, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Peng
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.|Xiangya Nursing School, Central South University, Changsha, Hunan, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Shao-Jie
authors.initials: SJ
authors.lastname: Yue
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.|Xiangya Nursing School, Central South University, Changsha, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Zhao
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Han
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.lastname: Yang-Li
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Qing-Mei
authors.initials: QM
authors.lastname: Cheng
authors.affiliation: Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhi-Guang
authors.initials: ZG
authors.lastname: Zhou
authors.affiliation: SBMS, The University of Queensland, Brisbane, Australia.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Feng
authors.affiliation: Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Zi-Qiang
authors.initials: ZQ
authors.lastname: Luo
mesh_terms: D000368:Aged; D000818:Animals; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000633:toxicity*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D018384:Oxidative Stress; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005947:Glucose