This study investigates the effects of antioxidants on the health-promoting benefits of physical exercise in humans. The researchers found that exercise increases insulin sensitivity and muscle gene expression related to insulin sensitivity and antioxidant defense, but these effects were significantly reduced when participants took antioxidant supplements (vitamin C and vitamin E). Specifically, exercise increased glucose infusion rates (GIR) and plasma adiponectin levels, which are markers of improved insulin sensitivity, only in individuals who did not take antioxidants. Additionally, exercise-induced increases in the expression of genes involved in insulin sensitivity, such as PGC1α, PGC1β, and PPARγ, were blocked by antioxidant supplementation. Similarly, exercise-induced increases in the expression of antioxidant defense enzymes, including SOD1, SOD2, and GPx1, were also prevented by antioxidants. The study suggests that antioxidants may hinder the beneficial effects of exercise on metabolism and insulin resistance, potentially due to the mitohormetic effects of transient oxidative stress.This study investigates the effects of antioxidants on the health-promoting benefits of physical exercise in humans. The researchers found that exercise increases insulin sensitivity and muscle gene expression related to insulin sensitivity and antioxidant defense, but these effects were significantly reduced when participants took antioxidant supplements (vitamin C and vitamin E). Specifically, exercise increased glucose infusion rates (GIR) and plasma adiponectin levels, which are markers of improved insulin sensitivity, only in individuals who did not take antioxidants. Additionally, exercise-induced increases in the expression of genes involved in insulin sensitivity, such as PGC1α, PGC1β, and PPARγ, were blocked by antioxidant supplementation. Similarly, exercise-induced increases in the expression of antioxidant defense enzymes, including SOD1, SOD2, and GPx1, were also prevented by antioxidants. The study suggests that antioxidants may hinder the beneficial effects of exercise on metabolism and insulin resistance, potentially due to the mitohormetic effects of transient oxidative stress.