Glucose oxidase induces insulin resistance via influencing multiple targets in聽vitro and in聽vivo: The central role of oxidative stress

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• 作者：Xin Wang¹ ; Chunshan Gu¹ ; Wei He ; Xiaolong Ye ; Hongli Chen ; Xiaodi Zhang ; Chunxu Hai ; ^{cx-hai@fmmu.edu.cn}
• 关键词：Glucose oxidase ; Insulin resistance ; ROS ; Oxidative stress
• 刊名：Biochimie
• 出版年：2012
• 期刊代码：24_03009084
• 类别：bio
• 出版时间：August, 2012
• 卷：94
• 期：8
• 页码：1705-1717
• 文件大小：1961 K

摘要

It is well known that reactive oxygen species (ROS) plays a role in the pathogenesis of insulin resistance which is the hallmark of type 2 diabetes. However, it is still needed to clarify the mechanism underlying insulin resistance. Glucose oxidase (GOD) is an oxi-reductase catalyzing the conversion of glucose to glucolactone, which is further converted to glucuronic acid and H₂O₂. The present study was designed to establish a rat model of insulin resistance using GOD and to investigate possible mechanisms. The results showed that three days administration of GOD could significantly increase fasting blood glucose, resulting in impaired glucose and insulin tolerance. Moreover, GOD disrupted insulin signaling both in rats and in hepatocytes, as evidenced by decreased phosphorylation of insulin-stimulated Akt, GSK3 and FOXO1伪. Furthermore, GOD administration decreased the expression of PPAR纬, alterated the phosphorylation of MAPKs, including p38, ERK and JNK, increased the expression of GRP78 and reduced the expression of PGC-1伪 and decreased the activities of ATPase and respiratory complexes, all of which have been reported to contribute to insulin resistance. Redox balance was evaluated by detecting the expression of antioxidant defenses and ROS generation. After the treatment with GOD, nuclear factorerythroid 2 p45-related factor 2 (Nrf2)-regulated antioxidant enzymes were damaged and ROS production increased significantly. N-acetyl-L-cysteine (NAC), a potent antioxidant, could notably inhibit these effects of GOD. Although further studies are needed to investigate the clear mechanism, these data also support the conclusion that, if not the most early event, ROS generation is the most important event that plays a central role in the pathogenesis of insulin resistance. Overall, our study established an insulin resistant animal model induced by GOD, elucidated the importance of ROS in pathogenesis of insulin resistance and provided the clue for further studies on the underlying mechanisms.