Effect of the interaction between diet composition and the PPM1K 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

Am J Clin Nutr. 2017 Sep;106(3):902-908. doi: 10.3945/ajcn.117.156281. Epub 2017 Aug 2.

Abstract

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.

Keywords: NUGENOB; gene-diet interaction; glucose concentrations; obesity; weight loss.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Amino Acids, Branched-Chain
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / genetics
  • Diet*
  • Dietary Carbohydrates / administration & dosage
  • Dietary Carbohydrates / pharmacology
  • Dietary Fats / administration & dosage
  • Dietary Fats / pharmacology
  • Feeding Behavior
  • Female
  • Gene-Environment Interaction*
  • Genotype
  • Humans
  • Insulin / blood
  • Insulin Resistance* / genetics
  • Insulin-Secreting Cells
  • Male
  • Middle Aged
  • Obesity* / blood
  • Obesity* / complications
  • Obesity* / diet therapy
  • Obesity* / genetics
  • Polymorphism, Single Nucleotide*
  • Protein Phosphatase 2C / genetics*
  • Weight Loss / physiology*

Substances

  • Amino Acids, Branched-Chain
  • Blood Glucose
  • Dietary Carbohydrates
  • Dietary Fats
  • Insulin
  • PPM1K protein, human
  • Protein Phosphatase 2C