dinediones (TZDs) are synthetic ligands of peroxisome proliferatoractivated receptor-␥ (PPAR␥), a member of the nuclear receptor superfamily. TZDs are known to increase insulin sensitivity and also to have an antioxidative effect. In this study, we tested whether TZDs protect pancreatic -cells from oxidative stress, and we investigated the mechanism involved in this process. To generate oxidative stress in pancreatic -cells (INS-1 and TC3) or isolated islets, glucose oxidase was added to the media. The extracellular and intracellular reactive oxygen species (ROS) were measured to directly determine the antioxidant effect of TZDs. The phosphorylation of JNK/MAPK after oxidative stress was detected by Western blot analysis, and glucose-stimulated insulin secretion and cell viability were also measured. TZDs significantly reduced the ROS levels that were increased by glucose oxidase, and they effectively prevented -cell dysfunction. The antioxidative effect of TZDs was abolished in the presence of a PPAR␥ antagonist, GW9662. Real-time PCR was used to investigate the expression levels of antioxidant genes. The expression of catalase, an antioxidant enzyme, was increased by TZDs in pancreatic -cells, and the knockdown of catalase significantly inhibited the antioxidant effect of TZDs. These results suggest that TZDs effectively protect pancreatic -cells from oxidative stress, and this effect is dependent largely on PPAR␥. In addition, the expression of catalase is increased by TZDs, and catalase, at least in part, mediates the antioxidant effect of TZDs in pancreatic -cells.peroxisome proliferator-activated receptor-␥; reactive oxygen species; catalase OXIDATIVE STRESS HAS BEEN IMPLICATED in the pathogenesis of type 2 diabetes and its vascular complications. Oxidative stress plays an important role in the development of -cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. It is well known that excessive reactive oxygen species (ROS) cause -cell dysfunction, such as defects in insulin synthesis and secretion, and apoptosis (9, 23, 32). Pancreatic -cells are very susceptible to oxidative stress because the expression levels of antioxidant enzymes, including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), are relatively low in -cells (12, 39). There are several reports showing that the overexpression of antioxidant enzymes protects pancreatic -cells from oxidative stress-induced dysfunction (1). Exposure to a high level of glucose and/or free fatty acid (FFA) results in the dysfunction of isolated islet or -cells, such as a decrease in insulin release and apoptosis (33,36). An antioxidant N-acetyl-cysteine (NAC) protects -cells from the high-glucose-or high-fatinduced impairments (37). These results suggest that ROS are involved in the glucose/FFA-induced -cell dysfunction.Peroxisome proliferator-activated receptor-␥ (PPAR␥), a member of the nuclear receptor superfamily, is expressed predominantly in adipose tissue and plays an im...