Antioxidants for Early Treatment of Type 2 Diabetes in Rodents and Humans: Lost in Translation?

Abstract

Reactive oxygen species (ROS) are formed by virtually all tissues. In normal concentrations they facilitate many physiologic activities, but in excess they cause oxidative stress and tissue damage. Local antioxidant enzyme synthesis in cells is regulated by the cytoplasmic KEAP-1/ Nrf2 complex, which is stimulated by ROS, to release Nrf2 for entry into the nucleus where it upregulates antioxidant gene expression. Major antioxidant enzymes include glutathione peroxidase (GPx), catalase (CAT), superoxide dismutases (SOD), hemoxygenases (HO), and peroxiredoxins (Prdx). Notably, the pancreatic islet beta cell does not express GPx or CAT, which puts it at greater risk for ROS damage caused by postprandial hyperglycemia. Experimentally, overexpression of GPx in beta cell lines and isolated islets as well as in vivo studies using genetic models of type 2 diabetes, have demonstrated enhanced protection against hyperglycemia and oxidative stress. Oral treatment of diabetic rodents with Ebselen, a GPx mimetic that is approved for human clinical usereproduced these findings. Prdxs detoxify hydrogen peroxide and reduce lipid peroxides. This suggests that pharmacologic development of more potent, beta cell specific antioxidants could be valuable as a treatment for oxidative stress due to post-prandial hyperglycemia in early type 2 diabetes in humans.