Hotta M, Tashiro F, Ikegami H, Niwa H, Ogihara T, Yodoi J, Miyazaki J
Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka 565-0871, Japan.
J Exp Med. 1998 Oct 19;188(8):1445-51. doi: 10.1084/jem.188.8.1445.
The cytotoxicity of reactive oxygen intermediates (ROIs) has been implicated in the destruction of pancreatic beta cells in insulin-dependent diabetes mellitus (IDDM). Thioredoxin (TRX), a redox (reduction/oxidation)-active protein, has recently been shown to protect cells from oxidative stress and apoptosis. To elucidate the roles of oxidative stress in the development of autoimmune diabetes in vivo, we produced nonobese diabetic transgenic mice that overexpress TRX in their pancreatic beta cells. In these transgenic mice, the incidence of diabetes was markedly reduced, whereas the development of insulitis was not prevented. Moreover, induction of diabetes by streptozotocin, an ROI-generating agent, was also attenuated by TRX overexpression in beta cells. This is the first direct demonstration that an antioxidative and antiapoptotic protein protects beta cells in vivo against both autoimmune and drug-induced diabetes. Our results strongly suggest that oxidative stress plays an essential role in the destruction of beta cells by infiltrating inflammatory cells in IDDM.
活性氧中间体（ROIs）的细胞毒性与胰岛素依赖型糖尿病（IDDM）中胰腺β细胞的破坏有关。硫氧还蛋白（TRX）是一种具有氧化还原（还原/氧化）活性的蛋白质，最近已被证明可保护细胞免受氧化应激和凋亡。为了阐明氧化应激在体内自身免疫性糖尿病发展中的作用，我们制备了在胰腺β细胞中过表达TRX的非肥胖糖尿病转基因小鼠。在这些转基因小鼠中，糖尿病的发病率显著降低，而胰岛炎的发展并未得到预防。此外，链脲佐菌素（一种产生ROIs的药物）诱导的糖尿病也因β细胞中TRX的过表达而减弱。这是首次直接证明一种抗氧化和抗凋亡蛋白在体内可保护β细胞免受自身免疫性和药物诱导的糖尿病侵害。我们的结果强烈表明，氧化应激在IDDM中通过浸润性炎症细胞破坏β细胞的过程中起着至关重要的作用。
