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.
Highlights
It is estimated that ∼11% of people in the United States aged 20 years or older have diagnosed or undiagnosed type 2 diabetes mellitus (T2D), and 35% of adults in the same age group are estimated to have prediabetes based on fasting glucose or hemoblogin A1c levels (Centers for Disease Control and Prevention, 2014)
The metabolites and biological pathways identified in our study provide information about signatures of metformin exposure and pharmacologic action
We first discuss our results in the context of exposure to metformin followed by its effects on glucose concentrations following an oral glucose tolerance test (OGTT)
Summary
It is estimated that ∼11% of people in the United States aged 20 years or older have diagnosed or undiagnosed type 2 diabetes mellitus (T2D), and 35% of adults in the same age group are estimated to have prediabetes based on fasting glucose or hemoblogin A1c levels (Centers for Disease Control and Prevention, 2014). Pharmacometabolomics of Metformin for the control of T2D, and is being investigated for its potential beneficial effects in the prevention or treatment of other diseases, such as a wide-ranging number of cancers (Evans et al, 2005; Zakikhani et al, 2006, 2008; Duncan and Schmidt, 2009). Metformin has been shown to impact the adenosine-5-phosphate kinase (AMPK) signaling pathway (Zhou et al, 2001), which is thought to be an important component in metformin’s glucoselowering mechanism. Other pathways, such as the mTOR pathway have been implicated in the beneficial effects of metformin including its antiproliferative effects in cancer treatment (Sahra et al, 2011). Understanding the complex mechanisms of action of metformin is of particular interest as it may lead to validated biomarkers that can be used to identify individuals most likely to respond to the drug, as well as those most likely to experience adverse drug effects
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