Switching from singlet-oxygen-mediated oxidation to free-radical-mediated oxidation in the pathogenesis of type 2 diabetes in model mouse

Abstract

Oxidative stress plays a key role in the development of type 2 diabetes. However, it is still unknown what kind of oxidative stress underlies the development of type 2 diabetes. We investigated hydroxyoctadecadienoic acid (HODE) isomers, which have been proposed as a biomarker for evaluating oxidative stress in vivo, during the development of diabetes in Tsumura Suzuki Obese Diabetes (TSOD) mouse, a type 2 diabetes model. It was revealed that glucose tolerance and insulin resistance index HOMA-IR in TSOD mice at 5 weeks of age were approximately normal, namely, the mice were in the prediabetic state, but these levels were significantly exacerbated from 8 weeks of age compared with those in Tsumura Suzuki Non Obesity (TSNO) mice (control). Concomitantly, the plasma levels of free-radical-mediated oxidation products, 9- and 13-(E,E)-HODE and 7β-hydroxycholesterol, in TSOD mice were significantly higher than those in TSNO mice at 8, and 8 and 11 weeks of age, respectively. Interestingly, the plasma levels of 10- and 12-(Z,E)-HODE, which are produced specifically by singlet-oxygen-mediated oxidation, in TSOD mice were higher than those in TSNO mice only at 5 weeks of age, and not at 8, 11, and 13 weeks of age. We demonstrated that singlet-oxygen-mediated oxidation occurred in TSOD mice before development of the diabetic phenotypes, including impaired glucose tolerance and insulin resistance. These results suggest that excessive singlet-oxygen-mediated oxidation plays an important role in the pathogenesis of type 2 diabetes.

Keywords::

• type 2 diabetes
• oxidative stress
• singlet oxygen
• free radical
• TSOD mouse

Acknowledgements

We thank Y. Fujita of AIST for technical assistance; Y. Senba of JAC Co., Ltd., for supporting animal care; and Dr. W. Suzuki of Tsumuro Co., Ltd., Dr. T. Ito of Yamagata University, and Dr. K. Ohwada of AIST for valuable suggestions and discussion. This work was supported by a Grant-in-Aid for Young Scientist (B) (no. 25860183 to K.M.) from the Japan Society for the Promotion of Science (JSPS), and partially supported by a grant from Foundation, Oil & Fat Industry Kaikan.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.