X. Liang,1 N. Oki,2 S. Yee,1 D. Rotroff,3 M. Meisner,3 O. Fiehn,4 K. Giacomini,1 R. Kaddurah-Daouk,2 Pharmacometabolomics Research Network; 1University of California, San Francisco, San Francisco, CA, 2Duke University Medical Center, Durham, NC, 3North Carolina State University, Raleigh, NC, 4West Coast Metabolomics Center, University of California, Davis, Davis, CA

BACKGROUND: Besides the anti-glycemic effect, metformin has beneficial effects on the cardiovascular system, polycystic ovary syndrome, and tumor prevention. Here, we used metabolomic approaches to investigate the global changes of metabolites in plasma in response to metformin treatment in healthy volunteers. The significantly changed metabolites lead to new insights into metformin mechanism. Also, these metabolic signatures may be used as early biomarkers of metformin response.
METHODS: a) 33 healthy African-American subjects were given two oral doses of metformin (1000 and 850 mg). b) Fasting baseline and two plasma samples at two times after metformin dosing were selected. c) Measurement was used mass spectrometry based GC-TOF. d) Metabolites and metformin exposure analysis: Wilcoxon paired t-test, Spearman’s rank correlation, and linear regression; Pathway analysis: Human Metabolome Database (v3.5).
RESULTS: Compared to baseline, 39 metabolites were significantly changed at peak metformin concentrations in plasma. 26 were structurally identified. The top known metabolites were hypoxanthine, maltose, citrulline, ribose, tyrosine, and ornithine (q value<0.008). These metabolites were implicated in various pathways including the urea cycle, cysteine metabolism, amino-sugar metabolism, and glucose-alanine cycle. Interestingly, 5 metabolites were overlapped in the urea cycle (25% enrichment).
CONCLUSION: Metformin treatment produces significant changes in plasma metabolite levels implicating multiple metabolic pathways. The urea cycle, associated with protein degradation, was the most significantly impacted. It suggests that in addition to regulating lipid and carbohydrate metabolism, metformin has effects on protein metabolism, previously not appreciated.