The Pro(12)-> Ala substitution in PPAR-gamma is associated with resistanceto 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 Pro12Ala substitution in peroxisome proliferat or-activated receptor-gamma differ among ethnic groups, and its relationshi p with diabetes and associated diseases is controversial, The prevalence of this polymorphism and its effects on clinical characteristics have now bee n evaluated with a large number of Japanese individuals with type 2 diabete s (n = 2,201) and normal control subjects (n = 1,212) recruited by 10 insti tutions located in seven different cities in Japan. The allele frequency fo r 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 Ala12, variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total chole sterol (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 Ala12 variant is ass ociated 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 an d disease severity in individuals with type 2 diabetes.