- Background: Common genetic variants in the Insulin receptor substrate 1 (IRS1) gene have been recently associated with insulin resistance and hyperinsulinemia. It is currently unknown whether genetic variants inluence insulin resistance by dietary response. Methods and Results: We genotyped IRS1 rs2943641 in 263 overweight adults randomly assigned to either low fat, low carbohydrate or Mediterranean diets in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) study. We assessed the progress in fasting insulin, insulin resistance (HOMA-IR) and weight loss by genotypes. There was signiicant interactions between IRS1 rs2943641 genotype and type of dietary intervention on changes in fasting insulin (P=0.004 for interaction) and HOMA-IR (P=0.013 for interaction) at 2 years. For example: participants with CC wildtype genotype had greater decreases in insulin resistance (HOMA-IR) than those without this genotype in the low-fat diet group, while an opposite effect was observed on the non-wild type allele carriers (CT+TT) (P=0.01). Our results recapitulated the recently published results of the Pound Loss study  Conclusions: In this generic-intervention trial, we found a genetic predisposition affecting insulin levels and insulin resistance after dietary intervention. This is demonstrated by different response to various types of diet among carriers of the wild type and non-wild type IRS1 rs2943641 allele.