Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues
Open accessAbstract
Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (ndt-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with ndt-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived from multiple murine tissues corroborated and complemented the findings from the human cohort.
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The metabolomics data link lowering of citrulline to an increase in NO generation from arginine and improved eNOS activity, supporting that metformin protects the cardiovascular system via promoting NO generation.
“The metabolomics data can links the lowering of citrulline to the increase in NO generation from arginine and improved eNOS activity, thus providing support to the literature that metformin protects the cardiovascular system via promoting the generation of NO (175).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [175]
Data from a metabolomics analysis of T2DM patients treated with metformin indicated that levels of the amino acid citrulline were lower than controls, with comparable data from tissues from the db/db mouse model.
“Data from a metabolomics analysis of T2DM patients treated with metformin has indicated that levels of the amino acid citrulline were lower than controls with comparable data from tissues from the db/db mouse model of T2DM and obesity.”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [175]
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- Authors
- Adam, J., Brandmaier, S., Leonhardt, J., Scheerer, M. F., Mohney, R. P., Xu, T., Bi, J., Rotter, M., Troll, M., Chi, S., Heier, M., Herder, C., Rathmann, W., Giani, G., Adamski, J., Illig, T., Strauch, K., Li, Y., Gieger, C., Peters, A., Suhre, K., Ankerst, D., Meitinger, T., Hrabĕ de Angelis, M., Roden, M., Neschen, S., Kastenmüller, G., & Wang-Sattler, R.
- Affiliations
- Helmholtz Munich (DE)
- Metabolon (United States) (US)
- Chinese Academy of Sciences (CN)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Medizinische Hochschule Hannover (DE)
- Harvard University (US)
- Technical University of Munich (DE)
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
- ShanghaiTech University (CN)
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-09-12
- Volume
- 65
- Issue
- 12
- Pages
- 3776-3785
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2520708667
- Cited by
- 68
- References
- 51
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 7 · 2021: 11 · 2020: 8 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 2
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- green
- mediatum.ub.tum.de
- Licence
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Seventh Framework Programme (HEALTH-2009-2.2.1-3/242114 (Project OPTiMiSE), HEALTH-2013-2.4.2-1/602936 (Project CarTarDis))
- Bundesministerium für Gesundheit
- Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia
- Deutsche Forschungsgemeinschaft (DFG; RA 459/3-1)
- Weill Cornell Medical College
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- metformin, type 2 diabetes, untargeted metabolomics, citrulline, pleiotropic drug effects, urea cycle, db/db mice, skeletal muscle, adipose tissue, liver, serum metabolites, KORA cohort
- MeSH terms
- Adipose Tissue, Animals, Citrulline, Diabetes Mellitus, Type 2, Fasting, Humans, Hypoglycemic Agents, Insulin Resistance, Longitudinal Studies, Male, Metformin, Models, Biological, Muscle, Skeletal, Mice
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