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Objective: Recent advances in type 2 diabetes genetics have culminated in the discovery and confirmation of multiple risk variants. Two important and largely unanswered questions are whether this information can be used to identify individuals most susceptible to the adverse consequences of sedentary behavior and to predict their response to lifestyle intervention; such evidence would be mechanistically informative and provide a rationale for targeting genetically susceptible subgroups of the population., Research Design and Methods: Gene x physical activity interactions were assessed for 17 polymorphisms in a prospective population-based cohort of initially nondiabetic middle-aged adults. Outcomes were 1) impaired glucose regulation (IGR) versus normal glucose regulation determined with either fasting or 2-h plasma glucose concentrations (n = 16,003), 2) glucose intolerance (in mmol/l, n = 8,860), or 3) incident type 2 diabetes (n = 2,063 events)., Results: Tests of gene x physical activity interactions on IGR risk for 3 of the 17 polymorphisms were nominally statistically significant:CDKN2A/B rs10811661 (P(interaction) = 0.015), HNF1B rs4430796 (P(interaction) = 0.026), and PPARG rs1801282 (P(interaction) = 0.04). Consistent interactions were observed for the CDKN2A/B (P(interaction) = 0.013) and HNF1B (P(interaction) = 0.0009) variants on 2-h glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed, and this was for the HNF1B rs4430796 variant (P(interaction) = 0.0004). The interaction effects for HNF1B on IGR risk and incident diabetes remained significant after correction for multiple testing (P(interaction) = 0.015 and 0.0068, respectively)., Conclusions: Our observations suggest that the genetic predisposition to hyperglycemia is partially dependent on a person's lifestyle.

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).

Exercise stimulates PGC-1alpha gene expression and increases V O2max, the latter of which relates inversely with type 2 diabetes risk. Consistently, low levels of PGC-1alpha mRNA and nucleotide sequence variation at PGC-1alpha associate with lower level of V O2max and increased diabetes risk. Thus, PGC-1alpha sequence variation may interact with physical activity to modify diabetes risk via changes in oxidative energy metabolism.