Insulin Receptor Substrate 1 Gene Variation Modifies Insulin Resistance Response to Weight-Loss Diets in a 2-year Randomized Trial: The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) Trial

Circulation. 2011 Aug 2;124(5):563-71. doi: 10.1161/CIRCULATIONAHA.111.025767. Epub 2011 Jul 11.


Background: Common genetic variants in the insulin receptor substrate 1 (IRS1) gene have been recently associated with insulin resistance and hyperinsulinemia. We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial.

Methods and results: We genotyped IRS1 rs2943641 in 738 overweight adults (61% were women) who were randomly assigned to 1 of 4 diets varying in macronutrient contents for 2 years. We assessed the progress in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and weight loss by genotypes. At 6 months, participants with the risk-conferring CC genotype had greater decreases in insulin (P=0.009), HOMA-IR (P=0.015), and weight loss (P=0.018) than those without this genotype in the highest-carbohydrate diet group whereas an opposite genotype effect on changes in insulin and HOMA-IR (P≤0.05) was observed in participants assigned to the lowest-carbohydrate diet group. No significant differences were observed across genotypes in the other 2 diet groups. The tests for genotype by intervention interactions were all significant (P<0.05). At 2 years, the genotype effect on changes in insulin and HOMA-IR remained significant in the highest-carbohydrate diet group (P<0.05). The highest carbohydrate diet led to a greater improvement of insulin and HOMA-IR (P for genotype-time interaction ≤0.009) in participants with the CC genotype than those without this genotype across 2-year intervention.

Conclusions: Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet.

Clinical trial registration: Unique identifier: NCT00072995.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Diet, Reducing / methods*
  • Dietary Carbohydrates / administration & dosage
  • Dietary Fats / therapeutic use
  • Dietary Proteins / therapeutic use
  • Energy Intake / genetics
  • Female
  • Genetic Variation
  • Genotype
  • Humans
  • Insulin / blood
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin Resistance / genetics*
  • Male
  • Middle Aged
  • Overweight / diet therapy*
  • Overweight / epidemiology
  • Overweight / genetics*
  • Risk Factors
  • Weight Loss / genetics*


  • Dietary Carbohydrates
  • Dietary Fats
  • Dietary Proteins
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins

Associated data