J. Exp. Med., Volume 188, Number 8, October 19, 1998 1445-1451

Pancreatic  Cell-specific Expression of  Thioredoxin, an Antioxidative and Antiapoptotic Protein, Prevents Autoimmune and Streptozotocin-induced Diabetes

By Mizuo Hotta,^* Fumi Tashiro,^* Hiroshi Ikegami, Hitoshi Niwa,^* Toshio Ogihara, Junji Yodoi,^§ and Jun-ichi Miyazaki^*

From the ^* Department of Nutrition and Physiological Chemistry, and the  Department of Geriatric Medicine, Osaka University Medical School, Osaka 565-0871, Japan; and the ^§ Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8397, Japan

The cytotoxicity of reactive oxygen intermediates (ROIs) has been implicated in the destruction of pancreatic  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  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  cells. This is the first direct demonstration that an antioxidative and antiapoptotic protein protects  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  cells by infiltrating inflammatory cells in IDDM.

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