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Pharmacometabolomic assessment of metformin in non-diabetic, African Americans

Publication ,  Journal Article
Rotroff, DM; Oki, NO; Liang, X; Yee, SW; Stocker, SL; Corum, DG; Meisner, M; Fiehn, O; Motsinger-Reif, AA; Giacomini, KM; Kaddurah-Daouk, R
Published in: Frontiers in Pharmacology
June 14, 2016

Millions of individuals are diagnosed with type 2 diabetes mellitus (T2D), which increases the risk for a plethora of adverse outcomes including cardiovascular events and kidney disease. Metformin is the most widely prescribed medication for the treatment of T2D; however, its mechanism is not fully understood and individuals vary in their response to this therapy. Here, we use a non-targeted, pharmacometabolomics approach to measure 384 metabolites in 33 non-diabetic, African American subjects dosed with metformin. Three plasma samples were obtained from each subject, one before and two after metformin administration. Validation studies were performed in wildtype mice given metformin. Fifty-four metabolites (including 21 unknowns) were significantly altered upon metformin administration, and 12 metabolites (including six unknowns) were significantly associated with metformin-induced change in glucose (q < 0.2). Of note, indole-3-acetate, a metabolite produced by gut microbes, and 4-hydroxyproline were modulated following metformin exposure in both humans and mice. 2-Hydroxybutanoic acid, a metabolite previously associated with insulin resistance and an early biomarker of T2D, was positively correlated with fasting glucose levels as well as glucose levels following oral glucose tolerance tests after metformin administration. Pathway analysis revealed that metformin administration was associated with changes in a number of metabolites in the urea cycle and in purine metabolic pathways (q < 0.01). Further research is needed to validate the biomarkers of metformin exposure and response identified in this study, and to understand the role of metformin in ammonia detoxification, protein degradation and purine metabolic pathways.

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Published In

Frontiers in Pharmacology

DOI

EISSN

1663-9812

Publication Date

June 14, 2016

Volume

7

Issue

JUN

Related Subject Headings

  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences
 

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Rotroff, D. M., Oki, N. O., Liang, X., Yee, S. W., Stocker, S. L., Corum, D. G., … Kaddurah-Daouk, R. (2016). Pharmacometabolomic assessment of metformin in non-diabetic, African Americans. Frontiers in Pharmacology, 7(JUN). https://doi.org/10.3389/fphar.2016.00135
Rotroff, D. M., N. O. Oki, X. Liang, S. W. Yee, S. L. Stocker, D. G. Corum, M. Meisner, et al. “Pharmacometabolomic assessment of metformin in non-diabetic, African Americans.” Frontiers in Pharmacology 7, no. JUN (June 14, 2016). https://doi.org/10.3389/fphar.2016.00135.
Rotroff DM, Oki NO, Liang X, Yee SW, Stocker SL, Corum DG, et al. Pharmacometabolomic assessment of metformin in non-diabetic, African Americans. Frontiers in Pharmacology. 2016 Jun 14;7(JUN).
Rotroff, D. M., et al. “Pharmacometabolomic assessment of metformin in non-diabetic, African Americans.” Frontiers in Pharmacology, vol. 7, no. JUN, June 2016. Scopus, doi:10.3389/fphar.2016.00135.
Rotroff DM, Oki NO, Liang X, Yee SW, Stocker SL, Corum DG, Meisner M, Fiehn O, Motsinger-Reif AA, Giacomini KM, Kaddurah-Daouk R. Pharmacometabolomic assessment of metformin in non-diabetic, African Americans. Frontiers in Pharmacology. 2016 Jun 14;7(JUN).

Published In

Frontiers in Pharmacology

DOI

EISSN

1663-9812

Publication Date

June 14, 2016

Volume

7

Issue

JUN

Related Subject Headings

  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences