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.

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: http:www.clinicaltrials.gov. Unique identifier: NCT00072995.

Figures

Figure 1. Genotype Effect of IR1 rs2943641 on Trajectory of Changes in Weight, Fasting Insulin and HOMA-IR in Participants Assigned to the Highest-carbohydrate Diet overall 2 Years

A: changes in weight, data were included for 187, 162 and 158 participants at baseline, 6 months and 2 years, respectively. B: changes in fasting insulin, data were included for 185, 150 and 135 participants at baseline, 6months and 2 years, respectively. C: changes in HOMA-IR, data were included for 185, 150 and 135 participants at baseline, 6months and 2 years, respectively. Data are means ± SE after adjustment for age, sex and ethnicity. P values were tested for the interaction between genotype and intervention time. Insulin and HOMA-IR were log-transformed before analysis.

Figure 2. Effect of the Highest-carbohydrate and the Lowest-carbohydrate Diets on Changes in Weight (A), Fasting Insulin (B) and HOMA-IR (C) by IRS1 Genotypes at 6 Months and 2 Years

Data are means ± SE and P-values are for comparisons between the 2 extreme diet groups, after adjustment for age, sex and ethnicity. Insulin and HOMA-IR were log-transformed before analysis.