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Xu, T. ; Brandmaier, S. ; Messias, A.C. ; Herder, C.* ; Draisma, H.H.* ; Demirkan, A.* ; Yu, Z. ; Ried, J.S. ; Haller, T.* ; Heier, M. ; Campillos, M. ; Fobo, G. ; Stark, R.G. ; Holzapfel, C.* ; Adam, J. ; Chi, S. ; Rotter, M. ; Panni, T. ; Quante, A.S. ; He, Y.* ; Prehn, C. ; Römisch-Margl, W. ; Kastenmüller, G. ; Willemsen, G.* ; Pool, R.* ; Kasa, K.* ; van Dijk, K.W.* ; Hankemeier, T.* ; Meisinger, C. ; Thorand, B. ; Ruepp, A. ; Hrabě de Angelis, M. ; Li, Y.* ; Wichmann, H.-E. ; Stratmann, B.* ; Strauch, K. ; Metspalu, A.* ; Gieger, C. ; Suhre, K. ; Adamski, J. ; Illig, T. ; Rathmann, W.* ; Roden, M.* ; Peters, A. ; van Duijn, C.M.* ; Boomsma, D.I.* ; Meitinger, T. ; Wang-Sattler, R.

Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.

Diabetes Care 38, 1858-1867 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.  
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0149-5992
e-ISSN 1935-5548
Journal Diabetes Care
Quellenangaben Volume: 38, Issue: 10, Pages: 1858-1867 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, Va.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Structural Biology (STB)
Institute of Experimental Genetics (IEG)
Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Genetic Epidemiology (IGE)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Human Genetics (IHG)