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Original Research
Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes
Tao Xu, Stefan Brandmaier, Ana C. Messias, Christian Herder, Harmen H.M. Draisma, Ayse Demirkan, Zhonghao Yu, Janina S. Ried, Toomas Haller, Margit Heier, Monica Campillos, Gisela Fobo, Renee Stark, Christina Holzapfel, Jonathan Adam, Shen Chi, Markus Rotter, Tommaso Panni, Anne S. Quante, Ying He, Cornelia Prehn, Werner Roemisch-Margl, Gabi Kastenmüller, Gonneke Willemsen, René Pool, Katarina Kasa, Ko Willems van Dijk, Thomas Hankemeier, Christa Meisinger, Barbara Thorand, Andreas Ruepp, Martin Hrabé de Angelis, Yixue Li, H.-Erich Wichmann, Bernd Stratmann, Konstantin Strauch, Andres Metspalu, Christian Gieger, Karsten Suhre, Jerzy Adamski, Thomas Illig, Wolfgang Rathmann, Michael Roden, Annette Peters, Cornelia M. van Duijn, Dorret I. Boomsma, Thomas Meitinger, Rui Wang-Sattler
Diabetes Care 2015 Jul; dc150658. https://doi.org/10.2337/dc15-0658
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Abstract

OBJECTIVE Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin.

RESEARCH DESIGN AND METHODS We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways.

RESULTS We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years’ follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target.

CONCLUSIONS Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.

  • Received March 30, 2015.
  • Accepted June 24, 2015.
  • © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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Diabetes Care: 44 (3)

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March 2021
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Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes
Tao Xu, Stefan Brandmaier, Ana C. Messias, Christian Herder, Harmen H.M. Draisma, Ayse Demirkan, Zhonghao Yu, Janina S. Ried, Toomas Haller, Margit Heier, Monica Campillos, Gisela Fobo, Renee Stark, Christina Holzapfel, Jonathan Adam, Shen Chi, Markus Rotter, Tommaso Panni, Anne S. Quante, Ying He, Cornelia Prehn, Werner Roemisch-Margl, Gabi Kastenmüller, Gonneke Willemsen, René Pool, Katarina Kasa, Ko Willems van Dijk, Thomas Hankemeier, Christa Meisinger, Barbara Thorand, Andreas Ruepp, Martin Hrabé de Angelis, Yixue Li, H.-Erich Wichmann, Bernd Stratmann, Konstantin Strauch, Andres Metspalu, Christian Gieger, Karsten Suhre, Jerzy Adamski, Thomas Illig, Wolfgang Rathmann, Michael Roden, Annette Peters, Cornelia M. van Duijn, Dorret I. Boomsma, Thomas Meitinger, Rui Wang-Sattler
Diabetes Care Jul 2015, dc150658; DOI: 10.2337/dc15-0658

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Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes
Tao Xu, Stefan Brandmaier, Ana C. Messias, Christian Herder, Harmen H.M. Draisma, Ayse Demirkan, Zhonghao Yu, Janina S. Ried, Toomas Haller, Margit Heier, Monica Campillos, Gisela Fobo, Renee Stark, Christina Holzapfel, Jonathan Adam, Shen Chi, Markus Rotter, Tommaso Panni, Anne S. Quante, Ying He, Cornelia Prehn, Werner Roemisch-Margl, Gabi Kastenmüller, Gonneke Willemsen, René Pool, Katarina Kasa, Ko Willems van Dijk, Thomas Hankemeier, Christa Meisinger, Barbara Thorand, Andreas Ruepp, Martin Hrabé de Angelis, Yixue Li, H.-Erich Wichmann, Bernd Stratmann, Konstantin Strauch, Andres Metspalu, Christian Gieger, Karsten Suhre, Jerzy Adamski, Thomas Illig, Wolfgang Rathmann, Michael Roden, Annette Peters, Cornelia M. van Duijn, Dorret I. Boomsma, Thomas Meitinger, Rui Wang-Sattler
Diabetes Care Jul 2015, dc150658; DOI: 10.2337/dc15-0658
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© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.