Genetic susceptibility to diabetes and long-term improvement of insulin resistance and β cell function during weight loss: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial

Abstract

Background: Diet interventions have shown effectiveness in improving diabetes risk factors; however, little is known about whether the effects of diet intervention are different according to genetic susceptibility.

Objective: We examined interactions between weight-loss diets and the genetic risk score (GRS) for diabetes on 2-y changes in markers of insulin resistance and β cell function in a randomized controlled trial.

Design: Data from the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial were analyzed. A GRS was calculated on the basis of 31 diabetes-associated variants in 744 overweight or obese nondiabetic adults (80% white Americans). We assessed the changes in insulin resistance and β cell function over the 2-y intervention.

Results: Dietary protein significantly interacted with the diabetes GRS on fasting insulin, glycated hemoglobin (HbA1c), the homeostasis model assessment of β cell function (HOMA-B), and the homeostasis model assessment of insulin resistance (HOMA-IR) at 2 y in white Americans (P-interaction = 0.02, 0.04, 0.01, and 0.05, respectively). The lower GRS was associated with a greater decrease in fasting insulin (P = 0.04), HbA1c (P = 0.0001), and HOMA-IR (P = 0.02), and a lesser increase in HOMA-B (P = 0.004) in participants consuming a low-protein diet. Participants with a higher GRS might have a greater reduction in fasting insulin when consuming a high-protein diet (P = 0.03).

Conclusions: Our data suggest that individuals with a lower genetic risk of diabetes may benefit more from consuming a low-protein weight-loss diet in improving insulin resistance and β cell function, whereas a high-protein diet may be more beneficial for white patients with a higher genetic risk. This trial was registered at clinicaltrials.gov as NCT00072995.

Keywords: genetic risk score; gene–diet interaction; insulin resistance; weight-loss diets; β cell function.

FIGURE 1

Effects of the genetic risk score for diabetes and weight-loss diets on changes in fasting insulin and HOMA-IR during a 2-y intervention in white Americans. Values are means ± SEs. High-Pro group sample sizes: T1, n = 87; T2, n = 84; and T3, n = 63. Low-Pro group sample sizes: T1, n = 88; T2, n = 82; and T3, n = 67. The tertiles for the genetic risk score were defined in white Americans. To test for interactions, we examined genotype and genotype–diet interactions as independent predictors of changes in diabetes traits, adjusted for age, sex, ethnicity (in the whole population analysis), baseline weight, weight change, and the baseline value for the respective outcome trait in the generalized linear models. P-interaction refers to the interaction between protein diets and genetic risk score. P-trends across the tertile groups were tested in Low-Pro and High-Pro groups after adjustment for age, sex, weight change, and baseline values for respective phenotypes. Fasting insulin, HOMA-IR, HOMA-B, and HbA1c were log-transformed before analysis. HbA1c, glycated hemoglobin; High-Pro, high protein; HOMA-B, homeostasis model assessment of β cell function; Low-Pro, low protein; T, tertile.

FIGURE 2

Effects of the genetic risk score for diabetes on the trajectory of changes in fasting insulin and HOMA-IR in white Americans over 2 y in the Low-Pro group. Values are means ± SEs after adjustment for age, sex, weight change, and baseline values for respective phenotypes, n = 471 white Americans. Low-Pro group sample sizes—6 mo: T1, n = 100; T2, n = 99; and T3, n = 98; 24 mo: T1, n = 88; T2, n = 82; and T3, n = 67. P values were tested for the interaction between genotype and intervention time. Linear mixed models (PROC MIXED) were used to test the genotype effect on the trajectory of changes in diabetes traits. HbA1c, glycated hemoglobin; HOMA-B, homeostasis model assessment of β cell function; Low-Pro, low protein; T, tertile.