Genetic variation of fasting glucose and changes in glycemia in response to 2-year weight-loss diet intervention: the POUNDS LOST trial

Int J Obes (Lond). 2016 Jul;40(7):1164-9. doi: 10.1038/ijo.2016.41. Epub 2016 Mar 22.


Objective: Weight-loss intervention through diet modification has been widely used to improve obesity-related hyperglycemia; however, little is known about whether genetic variation modifies the intervention effect. We examined the interaction between weight-loss diets and genetic variation of fasting glucose on changes in glycemic traits in a dietary intervention trial.

Research design and methods: The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial is a randomized, controlled 2-year weight-loss trial. We assessed overall genetic variation of fasting glucose by calculating a genetic risk score (GRS) based on 14 fasting glucose-associated single nucleotide polymorphisms, and examined the progression in fasting glucose and insulin levels, and insulin resistance and insulin sensitivity in 733 adults from this trial.

Results: The GRS was associated with 6-month changes in fasting glucose (P<0.001), fasting insulin (P=0.042), homeostasis model assessment of insulin resistance (HOMA-IR, P=0.009) and insulin sensitivity (HOMA-S, P=0.043). We observed significant interaction between the GRS and dietary fat on 6-month changes in fasting glucose, HOMA-IR and HOMA-S after multivariable adjustment (P-interaction=0.007, 0.045 and 0.028, respectively). After further adjustment for weight loss, the interaction remained significant on change in fasting glucose (P=0.015). In the high-fat diet group, participants in the highest GRS tertile showed increased fasting glucose, whereas participants in the lowest tertile showed decreased fasting glucose (P-trend <0.001); in contrast, the genetic association was not significant in the low-fat diet group (P-trend=0.087).

Conclusions: Our data suggest that participants with a higher genetic risk may benefit more by eating a low-fat diet to improve glucose metabolism.

Trial registration: NCT00072995.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / genetics*
  • Blood Glucose / metabolism*
  • Diet, Reducing*
  • Fasting / metabolism*
  • Female
  • Genetic Variation*
  • Glycated Hemoglobin A / metabolism
  • Glycemic Index
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Male
  • Middle Aged
  • Obesity / complications
  • Obesity / diet therapy*
  • Obesity / epidemiology
  • Polymorphism, Single Nucleotide
  • Treatment Outcome
  • United States / epidemiology
  • Weight Loss / physiology*


  • Blood Glucose
  • Glycated Hemoglobin A
  • Insulin
  • hemoglobin A1c protein, human

Associated data