Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes

Abstract

Unbiased, "nontargeted" metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.

Keywords: Cardiology; Diabetes; Diagnostics; Metabolism.

Figure 1. m/z 202.1185 is associated with the gene AGXT2.

Manhattan plot of the GWAS for m/z 202.1185 revealed an association with several SNPs at the AGXT2 locus. See also Supplemental Figure 2.

Figure 2. Discovery and confirmation of the identity of m/z 202.1185 as DMGV.

(A) Schematic illustration of the transamination of ADMA to DMGV by AGXT2. (B) The chromatographic RT of m/z 202.1185 matches exactly that of the DMGV standard. (C) The MS/MS fragmentation spectrum of m/z 202.1185 matches exactly that of the DMGV standard. See also Supplemental Figures 1 and 3.

Figure 3. DMGV levels are elevated in biopsy-proven NASH and are modulated following weight loss surgery.

(A) DMGV was significantly elevated in biopsy-proven NAFLD cases compared with controls (Mann-Whitney U test, n = 36 per group, 2.48 ± 1.31 vs. 1.71 ± 0.99 AU, P = 0.007). (B) Levels of DMGV at each time point before and after RYGB, demonstrating a significant reduction at 2 months and 6 months (paired t tests, n = 39, P = 0.01 and P = 0.0003, respectively). See also Supplemental Figures 1, 3, and 4.