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 β-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 β-cell lines and isolated islets, as well as in vivo studies using genetic models of type 2 diabetes (T2D), has demonstrated enhanced protection against hyperglycemia and oxidative stress. Oral treatment of diabetic rodents with ebselen, a GPx mimetic that is approved for human clinical use, reproduced these findings. Prdx detoxify hydrogen peroxide and reduce lipid peroxides. This suggests that pharmacologic development of more potent, β-cell–specific antioxidants could be valuable as a treatment for oxidative stress due to postprandial hyperglycemia in early T2D in humans. Article Highlights