Perspectives in Diabetes The Peroxisome Proliferator–Activated Receptor- 2 Pro12Ala Polymorphism

Peroxisome proliferator–activated receptor (PPAR)is a transcription factor with a key role in adipocyte differentiation. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR2 is associated with reduced risk for type 2 diabetes. The effect on the individual is weak, but because of a prevalence of >75% of the high-risk Pro allele, the population-attributable risk is enormous. The in vivo effects of the polymorphism are secondary to alterations in adipose tissue, where PPAR2 is predominantly expressed. Moderate reduction in transcriptional activity of PPARas a result of the polymorphism modulates production and release of adipose-derived factors. Both decreased release of insulin-desensitizing free fatty acids, tumor necrosis factor, and resistin and increased release of the insulin-sensitizing hormone adiponectin result in secondary improvement of insulin sensitivity of glucose uptake and suppression of glucose production. The population effect of this polymorphism may be modulated by environmental or genetic factors such as obesity, ethnicity, ratio of unsaturated to saturated fatty acids, and genetic background. Once diabetes has developed, the protective effect of the Ala allele may be lost, since increased vascular complications and more pronounced -cell dysfunction have been reported. These observations, however, are currently unexplained. In conclusion, the Pro12Ala polymorphism in PPAR2 represents the first genetic variant with a broad impact on the risk of common type 2 diabetes. The precise understanding of its mechanism may lead to novel diagnostic, preventive, and therapeutic approaches for improving the management of type 2 diabetes. Diabetes 51: 2341–2347, 2002 Peroxisome proliferator–activated receptor (PPAR)is a transcription factor that belongs to the same family of nuclear receptors as steroid and thyroid hormone receptors (1). It is activated by certain fatty acids, prostanoids, and thiazolidinediones, a novel class of insulin-sensitizing antidiabetic agents (2–4). Upon activation, it heterodimerizes with the retinoid X receptor and binds to specific PPAR-responsive elements of DNA to promote transcription of numerous target genes (5). Although the isoform PPAR1 is expressed in most tissues, PPAR2 is specific for adipose tissue, where it plays a key role in regulating adipogenic differentiation (6). The PPARgene is located on chromosome 3 (7), and the specific isoforms are a result of alternative mRNA splicing. A number of genetic variants in the PPARgene have been identified. These include a very rare gain-of-function mutation (Pro115Gln) associated with obesity but not insulin resistance (8), two loss-of-function mutations (Val290Met and Pro467Leu) reported in three individuals with severe insulin resistance but normal body weight (9), the silent CAC478CAT mutation (10–12), and the highly prevalent Pro12Ala polymorphism in PPAR2 (Fig. 1). The latter is the result of a CCA-to-GCA missense mutation in codon 12 of exon B of the PPARgene. This exon encodes the NH2-terminal residue that defines the adipocyte-specific PPAR2 isoform. The Pro12Ala polymorphism in PPAR2, which is the focus of this review, was first identified in 1997 (13), and the rare allele frequencies are 12% in Caucasians, 10% in Native Americans, 8% in Samoans, 4% in Japanese, 3% in African-Americans, 2% in Nauruans, and 1% in Chinese (14,15). In Caucasians, the ethnic group with the highest frequency, this translates into a carrier prevalence of the polymorphism of almost 25%.