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

Abstract

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) FamilyStudy, 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 MEASURESThe 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.

Dimethylguanidino valeric acid is independently associated with intrahepatic triglyceride content in patients with nonalcoholic fatty liver disease (NAFLD) and decreased after long-term exercise

“…Thus, in the present study, DMGV was used to evaluate the effect on metabolic changes under different exercise intensities. We found that DMGV concentration was decreased after 6 month exercise training, which was corresponding to another similar study 9 . Interestingly, compared to control, moderate exercise was much more e cient on decreasing DMGV than vigorous exercise with an equal effect on IHTG reduction, though vigorous exercise was more e cient on improvement of weight, waist circumference, body fat and visceral fat.…”

“…Moreover, DMGV was a bene cial metabolic intervention, since its level was decreased in participants after weight loss surgery. Recent study proposed that DMGV levels were positively associated with body fat, abdominal visceral fat, TG and an inverse associated with insulin sensitivity, LDL-C and HDL-C in healthy people 9 ; however, DMGV remains an incompletely understood metabolite with few data in NAFLD. For DMGV concentration quantitation in human serum in our study, LC condition, MS/MS parameters and serum sample preparation was carefully optimized, method validation was strictly performed.…”

“…With the development of analytical technologies, metabolomic study has been widely used to discover a panel of biomarkers in development and progression of NAFLD 6,7 . Recently, Targeted and non-targeted metabolomics studies has identi ed that circulating dimethylguanidino valeric acid (DMGV) was acted as a marker of liver fat and predicted future diabetes up to 12 years in 3 distinct human cohorts 8 , in addition, plasma DMGV levels had a strong relationship with visceral adiposity and decreased insulin sensitivity, and was recognized as an early marker of cardiometabolic dysfunction in health white people 9 . However, DMGV' character in NAFLD status and its response to exercise were limited.…”

Plasma Metabolites Associate with All-Cause Mortality in Individuals with Type 2 Diabetes

“…We now extend these findings by showing that levels of N2,N2-dimethylguanosine and DMGV also are associated with increased risk of all-cause mortality in individuals with diabetes. Both DMGV [10,16] and N2,N2-dimethylguanosine [11,17] have previously been shown to correlate strongly with CMD risk factors, such as obesity and dyslipidemia in healthy individuals. Furthermore, we showed that DMGV is very strongly correlated with HOMA-IR in individuals with diabetes.…”

Cardiometabolic non-response to aerobic exercise: Identifying subclinical ischaemic coronary disease

“…evaluated the effects of endurance exercise training on glucose homeostasis along with plasma levels of dimethylguanidino valeric acid (DMGV), insulin, lipids, lipoproteins, apolipoproteins and lipoprotein subclass and particle sizes. 2 These authors directly associated baseline DMGV levels with changes in small high-density lipoprotein (HDL) particles, and inversely related these levels to modifications in medium and total HDL particles, apolipoprotein A1 and insulin sensitivity after exercise training. Importantly, a diminished HDL particle number seems to work better than HDL-cholesterol levels for cardiovascular risk prediction.…”