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Abstract
Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide metformin is the most common pharmaceutical therapy. Yet its full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of nondiabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared with nondiabetic subjects, changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study.
SIGNIFICANCE STATEMENT This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.
Footnotes
- Received October 24, 2022.
- Accepted January 17, 2023.
This work was funded in part by the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service [I01 BX003700]; National Institutes of Health National Center for Advancing Translational Sciences [Grant UL1-TR002373], National Institute of Diabetes and Digestive and Kidney Diseases [Grants R01-DK102598, F31-DK109698], National Institute of General Medical Sciences [Grants R01-GM125085, T32-GM081061], National Heart, Lung, and Blood Institute [Grants R01-HL109810, F31-HL152647], and NIH Office of the Director [Grant S10-OD018475]; a UW2020 WARF Discovery Initiative Grant from the University of Wisconsin-Madison Office of the Vice Chancellor for Research and Graduate Education and the Wisconsin Alumni Research Foundation; and Research Starter Grant in Translational Medicine and Therapeutics from the PhRMA Foundation. A.W. was supported by a VA Advanced Fellowship in Women’s Health. S.P. was supported by a Pearl Stetler Research Fund for Women Physicians Fellowship.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, or the U.S. government. The study sponsors had no role in the study design; collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the paper for publication. No author has an actual or perceived conflict of interest with the contents of this article.
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- U.S. Government work not protected by U.S. copyright.
