The Pro12→Ala Substitution in PPAR-γ Is Associated With Resistance to Development of Diabetes in the General Population

Abstract

The allele frequencies for a Pro 12 3 Ala substitution in peroxisome proliferator-activated receptor-␥ 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. Diabetes 50:891-894, 2001

Influence of Pro12Ala peroxisome proliferator-activated receptor γ2 polymorphism on glucose response to exercise training in type 2 diabetes

“…This Pro 12 Ala SNP has been associated with reduced transcriptional activity in vitro [17]. Discordant results have been reported in the literature [17][18][19][20][21][22][23]; however, a recent meta-analyses of 16 studies, which included over 3,000 individuals, demonstrated that the Ala allele confers protection from diabetes (21% risk reduction) [24,25]. It is possible that the environment, particularly diet or exercise habits, could modify the genotype effect and may account for a portion of the disparity found between separate studies.…”

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

“…The 12Ala allele was associated with a higher reduction in the 2-h serum insulin level, probably indicating an increase in insulin sensitivity. However, it cannot be excluded that a decrease in insulin levels could also be due to impaired insulin secretion, because the 12Ala allele has been associated with reduced insulin secretion capacity in previous studies [20,47].…”

“…Therefore, the PPAR-γ gene has been viewed as a "thrifty gene", with an important role in the development of type 2 diabetes and diabetes-related traits [7,15]. Additionally, the Pro12Ala substitution in exon B of the PPAR-γ2 gene, first reported in Caucasians [16], has been associated with diabetes mellitus [17,18,19,20,21,22,23,24,25,26,27,28]. Although not all associations have been consistent, a meta-analysis of published studies has confirmed a modest (1.25-fold), but statistically significant, increase in diabetes risk for the Pro12Pro genotype [4,19].…”

Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene

“…All study subjects (n=549) were Japanese, unrelated and gave their written informed consent to participate in the study for the identification of Type II diabetes genes in Japan [23,24] [25]. The healthy control subjects were selected according to the following criteria: no past history of urinary sugar or of glucose intolerance, an HbA 1c level of less than 5.6%, an age of older than 60 years, and no family history of diabetes mellitus.…”

“…The healthy control subjects were selected according to the following criteria: no past history of urinary sugar or of glucose intolerance, an HbA 1c level of less than 5.6%, an age of older than 60 years, and no family history of diabetes mellitus. These criteria which could enhance statistical power to detect associations were also used in previous reports from our laboratory [23,24]. The investigation was carried out in accordance with the guidelines expressed in the Declaration of Helsinki.…”