title: Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans.
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.
authors.affiliation: Bioinformatics Research Center, North Carolina State UniversityRaleigh, NC, USA; Department of Statistics, North Carolina State UniversityRaleigh, NC, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rotroff
authors.affiliation: Bioinformatics Research Center, North Carolina State University Raleigh, NC, USA.
authors.forename: Noffisat O
authors.initials: NO
authors.lastname: Oki
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco, CA, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco, CA, USA.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco, CA, USA.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Stocker
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina Charleston, SC, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Corum
authors.affiliation: Department of Statistics, North Carolina State University Raleigh, NC, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Meisner
authors.affiliation: UC Davis Genome Center, University of California DavisDavis, CA, USA; Department of Biochemistry, King Abdulaziz UniversityJeddah, Saudi-Arabia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Statistics, North Carolina State UniversityRaleigh, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke UniversityDurham, NC, USA.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Motsinger-Reif
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco, CA, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke UniversityDurham, NC, USA; Duke Institute for Brain Sciences, Duke UniversityDurham, NC, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Kaddurah-Daouk
keywords: metabolism; metformin; pharmacometabolomics; precision medicine