We have investigated the role of PPARgamma and its related genes on the pathogenesis of type 2 diabetes. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARgamma agonist treatment. Moreover, a Pro12Ala polymorphism in the human PPARgamma 2 gene, which has been reported to cause a reduction in the PPARgamma activity, was associated with decreased risk of type 2 diabetes in Japanese. The protective effect of this polymorphism against type 2 diabetes has been confirmed by meta-analysis using reports in various ethnic groups. Taken together with these results, PPARgamma is a thrifty gene mediating type 2 diabetes both in mice and humans. Indeed, pharmacological inhibitors of PPARgamma/RXR ameliorates high-fat diet-induced insulin resistance in animal models of type 2 diabetes.