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Articles

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 β 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 β 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 β cells. This is the first direct demonstration that an antioxidative and antiapoptotic protein protects β 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 β cells by infiltrating inflammatory cells in IDDM.

Key Words: oxidative stress • nonobese diabetic mouse • insulitis • cytokine • apoptosis

Abbreviations used: B6, C57BL/6J; IDDM, insulin-dependent diabetes mellitus; NO, nitric oxide; NOD, nonobese diabetic; ROI, reactive oxygen intermediate; RT, reverse transcription; STZ, streptozotocin; TRX, thioredoxin; hprt, hypoxanthine-guanine phosphoribosyl transferase.

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