Men Xiuli, Wang Haiyan, Li Mi, Cai Hanqing, Xu Shiqin, Zhang Wenjian, Xu Yaping, Ye Liya, Yang Wenying, Wollheim Claes B, Lou Jinning
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, PR China.
Int J Biochem Cell Biol. 2009 Apr;41(4):879-90. doi: 10.1016/j.biocel.2008.08.031. Epub 2008 Sep 2.
The pancreatic beta cell dysfunction is critical cycle in the pathogenesis of diabetes. Hyperglycemia is one of factors that induce pancreatic beta cell dysfunction, but the underlying mechanisms have not been well elucidated. In this study, we reported that a mitochondrial fission modulator, Dynamin-related protein 1 (Drp-1), plays an important role in high glucose induced beta cell apoptosis. Drp-1 expressed in islet beta cells was increased drastically under hyperglycemia conditions. Induction of Drp-1 expression significantly promoted high glucose induced apoptosis in Drp-1WT (Drp-1 wild type) inducible beta cell line, but not in Drp-1K38A (a dominant negative mutant of Drp1) inducible beta cell line. We further demonstrated that mitochondrial fission, cytochrome C release, mitochondrial membrane potential decreased, caspase-3 activation and generation of reactive oxygen species were enhanced by induction of Drp-1WT, but prevented by Drp-1K38A in pancreatic beta cells under high glucose condition. These results indicated that Drp-1 mediates high glucose induced pancreatic beta cell apoptosis.
胰腺β细胞功能障碍是糖尿病发病机制中的关键环节。高血糖是诱导胰腺β细胞功能障碍的因素之一，但其潜在机制尚未完全阐明。在本研究中，我们报道了一种线粒体分裂调节剂——动力相关蛋白1（Drp-1），在高糖诱导的β细胞凋亡中起重要作用。在高血糖条件下，胰岛β细胞中Drp-1的表达显著增加。Drp-1表达的诱导显著促进了Drp-1野生型（Drp-1WT）诱导性β细胞系中高糖诱导的凋亡，但在Drp-1K38A（Drp1的显性负性突变体）诱导性β细胞系中则没有。我们进一步证明，在高糖条件下，Drp-1WT的诱导增强了胰腺β细胞中的线粒体分裂、细胞色素C释放、线粒体膜电位降低、caspase-3激活和活性氧的产生，但Drp-1K38A可阻止这些现象。这些结果表明，Drp-1介导了高糖诱导的胰腺β细胞凋亡。
