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

Abstract:

AIMS/HYPOTHESIS:Peroxisome proliferator-activated receptor gamma (PPARgamma), 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 < or = 0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p = 0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p = 0.04) was also observed, which was most evident with metformin treatment (p < 0.001). CONCLUSIONS/INTERPRETATION:Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992).

journal_name

Diabetologia

journal_title

Diabetologia

authors

Franks PW,Jablonski KA,Delahanty L,Hanson RL,Kahn SE,Altshuler D,Knowler WC,Florez JC,Diabetes Prevention Program Research Group.

doi

10.1007/s00125-007-0826-6

subject

Has Abstract

pub_date

2007-12-01 00:00:00

pages

2451-60

issue

12

eissn

0012-186X

issn

1432-0428

journal_volume

50

pub_type

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