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

ENDOCRINOLOGY(2017)

Cited 26|Views64
No score
Abstract
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.
More
Translated text
Key words
pancreatic nmdars,apoptosis,sustained activation
AI Read Science
Must-Reading Tree
Example
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined