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Front Pharmacol. 2016 Jun 14;7:135. doi: 10.3389/fphar.2016.00135. eCollection 2016.

Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans.

Author information

1
Bioinformatics Research Center, North Carolina State UniversityRaleigh, NC, USA; Department of Statistics, North Carolina State UniversityRaleigh, NC, USA.
2
Bioinformatics Research Center, North Carolina State University Raleigh, NC, USA.
3
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco, CA, USA.
4
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina Charleston, SC, USA.
5
Department of Statistics, North Carolina State University Raleigh, NC, USA.
6
UC Davis Genome Center, University of California DavisDavis, CA, USA; Department of Biochemistry, King Abdulaziz UniversityJeddah, Saudi-Arabia.
7
Department of Statistics, North Carolina State UniversityRaleigh, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke UniversityDurham, NC, USA.
8
Department of Psychiatry and Behavioral Sciences, Duke UniversityDurham, NC, USA; Duke Institute for Brain Sciences, Duke UniversityDurham, NC, USA.

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.

KEYWORDS:

metabolism; metformin; pharmacometabolomics; precision medicine

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