Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are insulin sensitizers, whereas PPAR alpha agonists are lipid-lowering agents in humans. Chronic treatment with PPAR gamma agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPAR alpha agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPAR alpha and nonthiazolidinedione (nTZD) PPAR gamma agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPAR gamma agonist completely prevented development of hyperglycemia, PPAR alpha activation was associated with lowering of food intake and body weight and reductions in fed and fasting hyperglycemia, with prevention of the hyperinsulinemic peak preceding the development of hyperglycemia in ZDF rats. Both compounds improved glucose tolerance during an oral glucose tolerance test with concomitant increases in insulin response. Such improvements of insulin secretion were associated with increased islet to total pancreatic area ratio and pancreatic insulin contents. Hyperinsulinemic-euglycemic clamp studies demonstrated that nTZD PPAR gamma reduced basal endogenous glucose production and increased insulin-stimulated glucose disposal, consistent with an improved insulin action as a cause of the improved glucose homeostasis. In contrast, activation of PPAR alpha did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPAR gamma agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPAR alpha agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPAR gamma agonist, the PPAR alpha agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPAR alpha agonists in the prevention of type 2 diabetes mellitus.