Effect of the interaction between diet composition and the genetic variant on insulin resistance and β cell function markers during weight loss: results from the Nutrient Gene Interactions in Human Obesity: implications for dietary guidelines (NUGENOB) randomized trial.

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 () gene has been related to elevated BCAA concentrations and risk of type 2 diabetes. In the present study, we tested whether dietary fat and carbohydrate intakes influenced the association between the rs1440581 genetic variant and glucose-metabolism traits during weight loss. The rs1440581 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. 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; = 0.03). In addition, significant gene-diet interactions were shown for the rs1440581 genetic variant in relation to changes in insulin and HOMA-B (-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; = 0.04) and HOMA-B (β ± SE: -13.2 ± 3.81; = 0.003). An opposite effect was observed in the low-fat diet group, although in this group the T allele was marginally ( = 0.10) and not significantly ( = 0.24) associated with insulin and HOMA-B, respectively. 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.