Pro12Ala variant at the peroxisome proliferator-activated receptor γ gene and change in obesity-related traits in the Diabetes Prevention Program

• Published in: Diabetologia 2007-12, Vol.50 (12), p.2451-2460
• Main Authors: Franks, P. W, Jablonski, K. A, Delahanty, L, Hanson, R. L, Kahn, S. E, Altshuler, D, Knowler, W. C, Florez, J. C
• Format: Article
• Language: English
• Subjects: Adult; Alanine - genetics; Amino Acid Substitution; Body Composition - drug effects; Body Composition - genetics; Chromans - therapeutic use; computed tomography; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - prevention & control; Dietary Fats - administration & dosage; Eating - drug effects; Eating - genetics; Female; Gene Frequency; Gene-environment interaction; Genotype; Humans; Hypoglycemic Agents - therapeutic use; Life Style; Male; Metformin - therapeutic use; Middle Aged; obesity; Obesity - complications; Obesity - genetics; Peroxisome proliferator-activated receptor γ; Placebos; PPAR gamma - genetics; PPARG; Proline - genetics; PUFA intake; Randomised clinical trial; subcutaneous fat; Thiazolidinediones - therapeutic use; visceral fat
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-007-0826-6

Aims/hypothesis Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA. Methods We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomised clinical trial of treatment with metformin (n = 989), troglitazone (n = 363) or lifestyle modification (n = 1,004) vs placebo (n = 1,000) for diabetes prevention in high-risk individuals. Results At baseline, Ala12 carriers had larger waists (p < 0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p = 0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p = 0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p = 0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p < 0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p = 0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p