A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of beta-Cell Apoptosis and Dysfunction

作者：Huang, Xiao-Ting; Yue, Shao-Jie; Li, Chen; Huang, Yan-Hong; Cheng, Qing-Mei; Li, Xiao-Hong; Hao, Cai-Xia; Wang, Ling-Zhi; Xu, Jian-Ping; Ji, Ming; Chen, Chen; Feng, Dan-Dan^*; Luo, Zi-Qiang^*

来源：Endocrinology, 2017, 158(11): 3900-3913.

DOI：10.1210/en.2017-00366

• IONOTROPIC GLUTAMATE RECEPTORS
• TYPE-2 DIABETES-MELLITUS
• OXIDATIVE STRESS
• INSULIN-SECRETION
• GLUCOSE-TOXICITY
• ISLET CELLS
• MECHANISM
• PATHWAYS
• DEATH
• HYPOGLYCEMIA

Type 2 diabetes, which features beta-cell failure, is caused by the decrease of beta-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional beta-cell mass. Strategies to prevent beta-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-D-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving beta-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on beta-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet beta-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic beta-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of beta-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in beta-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs beta-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor-kappa B partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and beta-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

• 出版日期2017-11
• 单位长治医学院; 中南大学