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PPARs are important regulators of lipid and glucose metabolism. Clinical trials assessing the efficacy of fibrates and thiazolidinediones in the treatment of dyslipidemia and insulin resistance and recent genetic studies evaluating the impact of genetic variation in genes encoding PPARs on prediabetic phenotypes, such as insulin resistance, β-cell dysfunction, subclinical inflammation, and ectopic lipid deposition, revealed the importance of these nuclear hormone receptors in human metabolic disease. These findings as well as novel aspects of the role of PPARs in human metabolism are summarized herein.