Distinct genetic subtypes of adiposity and glycemic changes in response to weight-loss diet intervention: the POUNDS Lost trial

Abstract

Purpose: Obesity is a heterogeneous condition and distinct adiposity subtypes may differentially affect type 2 diabetes risk. We assessed relations between genetically determined subtypes of adiposity and changes in glycemic traits in a dietary intervention trial.

Methods: The four genetic subtypes of adiposity including waist-hip ratio-increase only (WHRonly+), body mass index-increase only (BMIonly+), WHR-increase and BMI-increase (BMI+WHR+), and WHR-decrease and BMI-increase (BMI+WHR-) were assessed by polygenetic scores (PGSs), calculated based on 159 single nucleotide polymorphisms related to BMI and/or WHR. We examined the associations between the four PGSs and changes in fasting glucose, insulin, β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in 692 overweight participants (84% white Americans) who were randomly assigned to one of four weight-loss diets in a 2-year intervention trial.

Results: Higher BMI+WHR-PGS was associated with a greater decrease in 2-year changes in waist circumference in white participants (P = 0.002). We also found significant interactions between WHRonly+PGS and dietary protein in 2-year changes in fasting glucose and HOMA-B (P = 0.0007 and < 0.0001, respectively). When consuming an average-protein diet, participants with higher WHRonly+PGS showed less increased fasting glucose (β = - 0.46, P = 0.006) and less reduction in HOMA-B (β = 0.02, P = 0.005) compared with lower WHRonly+PGS. Conversely, eating high-protein diet was associated with less decreased HOMA-B among individuals with lower than higher WHRonly+PGS (β = - 0.02, P = 0.006).

Conclusions: Distinct genetically determined adiposity subtypes may differentially modify the effects of weight-loss diets on improving glucose metabolism in white Americans. This trial was registered at clinicaltrials.gov as NCT00072995.

Keywords: Adiposity subtypes; Body mass index; Gene–diet interaction; Glycemic traits; Polygenetic score; Waist–hip ratio.

Fig. 1

Effects of the WHRonly+ PGS and weight-loss diets on changes in fasting glucose and HOMA-B during the 2-year intervention in white participants. Values were means±SEs, adjusted for age, sex, baseline BMI, weight loss at 2 years, and baseline values of the respective outcomes in the general linear models. HOMA-B were log-transformed before analysis. High-Pro, high protein; Avg-Pro, average protein; HOMA-B, homeostasis model assessment of β cell function; T, tertile. Panel a: changes in glucose; panel b: changes in HOMA-B.

Fig. 2

WHRonly+ PGS with 2-year trajectory of changes in fasting glucose and HOMA-B in response to weight-loss diet in white participants. Values were means±SEs after adjustment for age, sex, baseline BMI, weight change, and baseline values for respective phenotypes. P values were tested for the interaction between PGS and intervention time. HOMA-B was log-transformed before analysis. HOMA-B, homeostasis model assessment of β cell function; T, tertile. Panel a: changes in glucose in high protein group; panel b: changes in glucose in average protein group; panel c: changes in HOMA-B in high protein group; panel d: changes in HOMA-B in average protein group.