The development of metabolic dysfunctions like diabetes and insulin resistance in mammals is regulated by a myriad of factors. Oxidative stress seems to play a central role in this process as recent evidence shows a general increase in oxidative damage and a decrease in oxidative defense associated with several metabolic diseases. These changes in oxidative stress can be directly correlated with increased fat accumulation, obesity and consumption of high calorie/high fat diets. Modulation of oxidant protection through either genetic mutation or treatment with antioxidants can significantly alter oxidative stress resistance and accumulation of oxidative damage in laboratory rodents. Antioxidant mutant mice have previously been utilized to examine the role of oxidative stress in other disease models, but have been relatively unexplored as models to study the regulation of glucose metabolism. In this review, we will discuss the evidence for oxidative stress as a primary mechanism linking obesity and metabolic disorders and whether alteration of antioxidant status in laboratory rodents can significantly alter the development of insulin resistance or diabetes.

Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases (Msr) reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA−/−) are prone to the development of high fat diet-induced insulin resistance and a reduced physiological insulin response compared to high fat-fed wild type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high fat-fed mice show similar reduction in insulin receptor function and the lack of MsrA further diminishes these functions. Together, these data demonstrate for the first time that MsrA plays a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation.

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