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.

Keywords: metabolism; metformin; pharmacometabolomics; precision medicine.

Figure 1

Diagram showing time point A, B, and C relative to metformin administration and oral glucose tolerance tests, OGTT.

Figure 2

Pathways significantly impacted following metformin administration and associated with metformin's effects on glucose levels after an oral glucose tolerance test in non-diabetic African-American subjects.

Figure 3

Correlation and clustering between significant metabolites from time interval A to B. The modules represent the grouping clusters of the metabolites. R, correlation coefficient (−1 < R < 1).

Figure 4

Correlation and clustering between significant metabolites from time interval B to C. The modules represent the grouping clusters of the metabolites. R, correlation coefficient (−1 < R < 1).

Figure 5

Correlation and clustering between significant metabolites from time interval A to C. The modules represent the grouping clusters of the metabolites. Shading represents the correlation coefficient (−1 < R < 1).