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Original Investigation
June 5, 2019

Association of Dimethylguanidino Valeric Acid With Partial Resistance to Metabolic Health Benefits of Regular Exercise

Author Affiliations
  • 1Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 2Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 3Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia
  • 4Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee
  • 5Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson
  • 6Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana
JAMA Cardiol. 2019;4(7):636-643. doi:10.1001/jamacardio.2019.1573
Key Points

Question  Is a circulating biomarker of visceral fat associated with metabolic health changes to endurance exercise training?

Findings  This combination of cross-sectional and longitudinal analyses of an existing exercise study assessed the association between a novel circulating marker of hepatic fat, dimethylguanidino valeric acid, and metabolic health traits before and after 20 weeks of endurance exercise training. Dimethylguanidino valeric acid levels identified individuals with metabolic dysfunction at a young age and are associated with an adverse response in high-density lipoprotein traits and insulin sensitivity to exercise training.

Meaning  Blood dimethylguanidino valeric acid levels may identify individuals less responsive to the metabolic health benefits of endurance exercise training.


Importance  Metabolic responses to exercise training are variable. Metabolite profiling may aid in the clinical assessment of an individual’s responsiveness to exercise interventions.

Objective  To investigate the association between a novel circulating biomarker of hepatic fat, dimethylguanidino valeric acid (DMGV), and metabolic health traits before and after 20 weeks of endurance exercise training.

Design, Setting, and Participants  This study involved cross-sectional and longitudinal analyses of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a 20-week, single-arm endurance exercise clinical trial performed in multiple centers between 1993 and 1997. White participants with sedentary lifestyles who were free of cardiometabolic disease were included. Metabolomic tests were performed using a liquid chromatography, tandem mass spectrometry method on plasma samples collected before and after exercise training in the HERITAGE study. Metabolomics and data analysis were performed from August 2017 to May 2018.

Exposures  Plasma DMGV levels.

Main Outcome and Measures  The association between DMGV levels and measures of body composition, plasma lipids, insulin, and glucose homeostasis before and after exercise training.

Results  Among the 439 participants included in analyses from HERITAGE, the mean (SD) age was 36 (15) years, 228 (51.9%) were female, and the median (interquartile range) body mass index was 25 (22-28). Baseline levels of DMGV were positively associated with body fat percentage, abdominal visceral fat, very low-density lipoprotein cholesterol, and triglycerides, and inversely associated with insulin sensitivity, low-density lipoprotein cholesterol, high-density lipoprotein size, and high-density lipoprotein cholesterol (range of β coefficients, 0.17-0.46 [SEs, 0.026-0.050]; all P < .001, after adjusting for age and sex). After adjusting for age, sex, and baseline traits, baseline DMGV levels were positively associated with changes in small high-density lipoprotein particles (β, 0.14 [95% CI, 0.05-0.23]) and inversely associated with changes in medium and total high-density lipoprotein particles (β, −0.15 [95% CI, −0.24 to −0.05] and −0.19 [95% CI, −0.28 to −0.10], respectively), apolipoprotein A1 (β, −0.14 [95% CI, −0.23 to −0.05]), and insulin sensitivity (β, −0.13; P = 3.0 × 10−3) after exercise training.

Conclusions and Relevance  Dimethylguanidino valeric acid is an early marker of cardiometabolic dysfunction that is associated with attenuated improvements in lipid traits and insulin sensitivity after exercise training. Levels of DMGV may identify individuals who require additional therapies beyond guideline-directed exercise to improve their metabolic health.