Background: Macronutrients regulate the gene expression of hepatic nuclear factor 1 alpha (HNF1A) which plays a key role in in the normal function of pancreatic beta cells and development of insulin resistance.
Objective: We aimed to determine whether weight loss diets varying in macronutrients modulate the effect of HNF1A genetic variant on weight loss and improvement of insulin resistance.
Methods: We analyzed the interaction between a diabetes-associated common variant in the HNF1A gene (rs7957197) and weight-loss diets on body weight and insulin resistance among 722 overweight/obese adults from a 2-year randomized weight-loss trial (POUNDS Lost). We then sought to validate the findings in an independent 2-year weight-loss trial (Dietary Intervention Randomized Controlled Trial; DIRECT), which involved 280 different overweight/obese adults.
Results: In the POUNDS LOST, we found fat diet significantly modified the genetic effect of HNF1A such that greater decreases in body weight and waist were observed in participants with the T allele than others among high-fat diet group (P <0.04 for both, P for interaction <0.006, We observed borderline significant interactions for improvement of fasting insulin and insulin resistance (P for interaction=0.07 and 0.06, respectively). We found similar gene-fat interactions in the DIRECT.
Conclusions: The consistent findings from two independent randomized intervention trials provide strong evidence that individuals with the HNF1A rs7957197 T allele may experience enhanced weight loss and improved insulin sensitivity as a result of hypocaloric, high-fat diets.