New pathogenesis of diabetes mellitus : Role of endoplasmic reticulum stress mediated apoptosis on pancreatic β-cells

越来越多的证据表明，内质网功能紊乱通过细胞凋亡机制导致细胞死亡。本研究旨在揭示内质网应激在糖尿病发病机制中的作用。秋田鼠是胰岛素2基因错义突变的糖尿病模型小鼠。这种突变可能导致胰岛素的严重构象变化，并扰乱内质网功能。在糖尿病早期的秋田小鼠胰腺中诱导内质网伴侣蛋白Bip和细胞凋亡因子CHOP的mRNAs。在杂合的秋田小鼠中破坏CHOP基因可以保护β细胞免受凋亡，从而推迟糖尿病的发生。突变的胰岛素在小鼠β细胞株MIN6细胞中过表达可诱导CHOP表达并导致细胞凋亡，提示β细胞内质网负荷过高可引起内质网应激并通过CHOP诱导细胞凋亡。12周龄时，OLETF大鼠的体重、血糖、血清胰岛素浓度均高于LETO大鼠。与LETO大鼠相比，OLETF大鼠β-细胞中BiP和CHOP基因表达增加，提示内质网应激介导的β-细胞凋亡途径参与了OLETF大鼠糖尿病的发病机制。

Accumulating evidences suggest that disturbance of endoplasmic function leads to cell death through apoptosis mechanism. This study was undertaken to reveal the role of endoplasmic reticulum stress in the pathogenesis of diabetes.The Akita mouse is a diabetic model mouse with a missense mutation in insulin 2 gene. This mutation may cause a heavy conformational change of insulin, and disturb endoplasmic reticulum function. The mRNAs of endoplasmic reticulum chaperone Bip and apoptosis factor CHOP were induced in the pancreas of Akita mouse at early stage of diabetes. Disruption of the CHOP gene in the heterozygous Akita mouse could protect β-cells from apoptosis, which delayed the onset of diabetes. Over expression of the mutant insulin in MIN6 cells, a mouse β-cell line, induced CHOP expression and led to apoptosis.These results suggested that endoplasmic reticulum overload in β-cells can cause endoplasmic reticulum stress and leads to apoptosis via CHOP induction in vivo.The endoplasmic reticulum stress was also evaluated in the type 2 diabetic model rat (OLETF) and control rat (LETO). The OLETF rat showed higher body weight, blood glucose, serum insulin concentration than those of LETO rat after 12 weeks of age. The OLETF rat showed higher expression of Bip and CHOP mRNAs in the β-cells than those in LETO rat.These results suggested that the pathway of endoplasmic reticulum stress mediated β-cell apoptosis was involved in the pathogenesis of diabetes in OLETF rat.This study suggests the importance of endoplasmic reticulum stress in the cause of diabetes.