Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been implicated in adipocyte differentiation. Recently it was reported that heterozygous deficiency of PPAR gamma led to the protection from high-fat diet-induced insulin resistance in an animal model. A Pro12Ala polymorphism has been detected in the human PPAR gamma 2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPAR gamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPAR gamma 2 polymorphism in Japanese diabetic and non-diabetic subjects. The frequency of Ala12 was significantly lower in the diabetic group. In an overweight or obese group, subjects with Ala12 were more insulin sensitive than those without. These results suggest that the PPAR gamma is a thrifty gene and that the Pro12Ala PPAR gamma 2 polymorphism protects against type 2 diabetes in the Japanese.