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。秋田小鼠是胰岛素2基因错义突变的糖尿病模型小鼠。该突变可能导致胰岛素构象发生严重变化，干扰内质网功能。糖尿病早期秋田小鼠胰腺中内质网伴侣Bip和凋亡因子CHOP的mRNA表达被诱导。杂合子秋田小鼠CHOP基因的破坏可以保护β细胞免于凋亡，从而延迟糖尿病的发病。在2型糖尿病模型大鼠（OLETF）和正常对照大鼠（LETO）中观察到内质网应激，并发现突变型胰岛素在MIN6细胞中的过表达可诱导CHOP表达并导致细胞凋亡，提示在体内β细胞中内质网超载可通过CHOP诱导而引起内质网应激并导致细胞凋亡。12周龄后OLETF大鼠体重、血糖、血清胰岛素浓度均高于LETO大鼠。OLETF大鼠胰岛β细胞Bip和CHOP mRNA的表达高于LETO大鼠，提示内质网应激介导的胰岛β细胞凋亡参与了OLETF大鼠糖尿病的发病过程，提示内质网应激在糖尿病发病中的重要作用。

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.