The Pro12 → Ala substitution in PPAR-γ is associated with resistance to development of diabetes in the general population : Possible involvement in impairment of insulin secretion in individuals with type 2 diabetes

The allele frequencies for a Pro 12 →Ala substitution in peroxisome proliferator–activated receptor-γ differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes ( n = 2,201) and normal control subjects ( n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala 12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala 12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol ( P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment ( P = 0.007), and tended to possess a higher level of HbA 1c . These data suggest that the Ala 12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes.