Background: Circulating
branched-chain amino acids (BCAAs) and
aromatic amino acids (AAAs) have been shown to be associated with
insulin resistance and diabetes risk. The common rs1440581 T allele in the
protein phosphatase Mg2+/Mn2+ dependent 1K (PPM1K) gene has been related to elevated BCAA concentrations and risk of
type 2 diabetes.Objective: In the present study, we tested whether
dietary fat and
carbohydrate intakes influenced the association between the rs1440581 PPM1K genetic variant and
glucose-metabolism traits during
weight loss.Design: The rs1440581 PPM1K genetic variant was genotyped in a total of 757 nondiabetic individuals who were randomly assigned to 1 of 2 energy-restricted diets that differed in macronutrient composition (
low-fat diet: 20-25% fat, 15%
protein, and 60-65%
carbohydrate; high-fat diet: 40-45% fat, 15%
protein, and 40-45%
carbohydrate). The changes in fasting
glucose, fasting
insulin,
insulin resistance (homeostasis model assessment of
insulin resistance) and homeostasis model assessment of β cell function (HOMA-B) were measured after a mean ± SD
weight loss of 6.8 ± 3.4 kg over 10 wk and analyzed according to the presence of the T allele of rs1440581.Results: The rs1440581 T allele was associated with a smaller improvement in
glucose concentrations after the 10-wk dietary intervention (β ± SE: 0.05 ± 0.02 mg/dL; P = 0.03). In addition, significant gene-diet interactions were shown for the rs1440581 PPM1K genetic variant in relation to changes in
insulin and HOMA-B (P-interaction = 0.006 and 0.002, respectively). In response to the high-fat diet, the T allele was associated with a higher reduction of
insulin (β ± SE: -0.77 ± 0.40 μU/mL; P = 0.04) and HOMA-B (β ± SE: -13.2 ± 3.81; P = 0.003). An opposite effect was observed in the
low-fat diet group, although in this group the T allele was marginally (P = 0.10) and not significantly (P = 0.24) associated with
insulin and HOMA-B, respectively.Conclusion:PPM1K rs1440581 may affect changes in
glucose metabolism during
weight loss, and this effect is dependent on
dietary fat and
carbohydrate intakes. This trial was registered at controlled-trials.com as ISRCTN25867281.