title: 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.
abstract: 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.
  
  
  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.
  
  
  BACKGROUND
  http:www.clinicaltrials.gov. Unique identifier: NCT00072995.
authors: Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Qibin
authors: Q
authors: Qi
authors: George A
authors: GA
authors: Bray
authors: Steven R
authors: SR
authors: Smith
authors: Frank B
authors: FB
authors: Hu
authors: Frank M
authors: FM
authors: Sacks
authors: Lu
authors: L
authors: Qi
mesh_terms: D000328:Adult; D004038:Diet, Reducing / Q000379:methods*; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004041:Dietary Fats / Q000627:therapeutic use; D004044:Dietary Proteins / Q000627:therapeutic use; D002149:Energy Intake / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000178:diet therapy* / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors; D015431:Weight Loss / Q000235:genetics*
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004044:Dietary Proteins; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins