Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans.
Article Details
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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.
Front Pharmacol. 2016 Jun 14;7:135. doi: 10.3389/fphar.2016.00135. eCollection 2016.
- PubMed ID
- 27378919 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Pharmaco-metabolomics
Drug Drug Groups Metabolite Change Description Metformin Approved Indole-3-acetate decreased Metformin decreases the level of Indole-3-acetate in the blood Metformin Approved Levoglucosan decreased Metformin decreases the level of Levoglucosan in the blood Metformin Approved Tyrosine decreased Metformin decreases the level of Tyrosine in the blood Metformin Approved Glycine decreased Metformin decreases the level of Glycine in the blood Metformin Approved Malic acid decreased Metformin decreases the level of Malic acid in the blood Metformin Approved Fumaric acid decreased Metformin decreases the level of Fumaric acid in the blood Metformin Approved Hypoxanthine increased Metformin increases the level of Hypoxanthine in the blood Metformin Approved Maltose increased Metformin increases the level of Maltose in the blood Metformin Approved Ribose increased Metformin increases the level of Ribose in the blood Metformin Approved Glutamic acid increased Metformin increases the level of Glutamic acid in the blood Metformin Approved Cellobiotol increased Metformin increases the level of Cellobiotol in the blood Metformin Approved Methionine sulfoxide decreased Metformin decreases the level of Methionine sulfoxide in the blood Metformin Approved Citrulline decreased Metformin decreases the level of Citrulline in the blood Metformin Approved Ornithine decreased Metformin decreases the level of Ornithine in the blood