Oxidative stress plays a fundamental role in the development of diabetes, which has become a great threaten for health in the whole world. In recent years, it has been found that, in addition to the effect on metabolism, insulin plays an antioxidant role. However, the effect of insulin on the whole antioxidant enzyme system, especially in vivo, is not completely understood. We note that, in vitro and in vivo, insulin administration could sequentially and transiently increase a battery of antioxidant enzymes through the activation of the key transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2). The sequential activation of extracellular signal-regulated kinases (ERK)-protein kinase B (Akt) pathway maybe required for insulin-induced enhancement of antioxidant defense regulated by Nrf2. Our observation leads to the hypothesis that insulin regulates the redox balance and insulin bolsters antioxidant defenses via the ERK-Akt-Nrf2 pathway.