Analysis of the mechanisms of pancreatic β-cells destruction by intra-cellular oxidative stress and endoplasmic reticulum stress, and its application for the diabetes treatment.

越来越多的证据表明，胰岛β细胞内氧化应激和内质网功能紊乱是胰岛β细胞功能障碍的新机制。为探讨线粒体活性氧和内质网应激在2型糖尿病发病中的作用，采用免疫组织化学方法检测了2型糖尿病模型小鼠（ob/ob和db/db）线粒体活性氧的变化。糖尿病小鼠胰腺线粒体生物合成标记物线粒体示踪红CC-1表达增加。采用RT-PCR基因表达方法检测2型糖尿病模型小鼠胰腺内质网应激。内质网应激相关基因Bip、PERK、Ire 1 α、Calnexin和Calreticulin的表达均高于非糖尿病对照组。锰超氧化物歧化酶转基因小鼠和Bip转基因小鼠已经产生，目前正在研究中。这些转基因小鼠可用于体内分析线粒体活性氧和内质网应激在2型糖尿病发病机制中的作用。本研究提示，线粒体和内质网应激产生的活性氧是治疗2型糖尿病的新靶点。2型糖尿病

Accumulating evidences suggest that intra-cellular oxidative stress and disturbance of endoplasmic function in pancreatic β-cells are new mechanisms of β-cell dysfunction. This study was undertaken to reveal the role of mitochondrial reactive oxygen species and endoplasmic reticulum stress in the pathogenesis of type 2 diabetes.The mitochondrial reactive oxygen species was evaluated in the type 2 diabetic model mice (ob/ob and db/db) by immunohistochemical method. The expression of mitotracker red CC-1 (maker of mitochondrial biogenesis) was increased in the pancreas of diabetic mice. The endoplasmic reticulum stress was also evaluated in the pancreas of type 2 diabetic model mice by RT-PCR gene expression method. The expressions of endoplasmic reticulum stress related genes (Bip, PERK, Ire1α, Calnexin and Calreticulin) were increased when compared with those of non-diabetic control mice. The manganese superoxide dismutase transgenic mice and the Bip transgenic mice have been generated and now under investigation. These transgenic mice are useful for the in vivo analysis of mitochondrial reactive oxygen species and endoplasmic reticulum stress in the pathogenesis of type 2 diabetes.These results suggest that mitochondrial biogenesis and endoplasmic reticulum stress are activated in the pancreatic β-cells of type 2 model mice.This study suggests that the reactive oxygen species from mitochondria and endoplasmic reticulum stress are the new target for the treatment of type 2 diabetes.