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Diabetes Care. 2015 Oct;38(10):1858-67. doi: 10.2337/dc15-0658. Epub 2015 Aug 5.

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

Author information

  • 1Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
  • 2Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 3Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany German Center for Diabetes Research, Düsseldorf, Germany.
  • 4Department of Biological Psychology, Faculty of Psychology and Education, VU University Amsterdam, Amsterdam, the Netherlands EMGO Institute for Health and Care Research, Amsterdam, the Netherlands Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
  • 5Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
  • 6Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 7Estonian Genome Center, University of Tartu, Tartu, Estonia.
  • 8Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
  • 9Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 10Institute of Health Economics and Health Care Management, Helmholtz Zentrum München, Neuherberg, Germany.
  • 11Else Kroener-Fresenius-Center for Nutritional Medicine, Faculty of Medicine, Technische Universität München, Munich, Germany.
  • 12Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
  • 13Shanghai Center for Bioinformation Technology, Shanghai, China Bioinformatics Center, Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 14Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • 15Department of Biological Psychology, Faculty of Psychology and Education, VU University Amsterdam, Amsterdam, the Netherlands EMGO Institute for Health and Care Research, Amsterdam, the Netherlands.
  • 16Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
  • 17Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
  • 18Faculty of Science, Leiden Academic Centre for Drug Research, Analytical BioSciences, the Netherlands.
  • 19Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany German Center for Diabetes Research, Neuherberg, Germany.
  • 20Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany.
  • 21Heart and Diabetes Center NRW, Diabetes Center, Ruhr-University Bochum, Bad Oeynhausen, Germany.
  • 22Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
  • 23Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany German Center for Diabetes Research, Neuherberg, Germany.
  • 24Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
  • 25Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
  • 26Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany German Center for Diabetes Research, Düsseldorf, Germany Department of Endocrinology and Diabetology, Medical Faculty, Düsseldorf, Germany.
  • 27Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research, Neuherberg, Germany Department of Environmental Health, Harvard School of Public Health, Boston, MA.
  • 28Neuroscience Campus Amsterdam, Amsterdam, the Netherlands Center for Medical Systems Biology, Leiden, the Netherlands.
  • 29Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Human Genetics, Technische Universität München, Munich, Germany.
  • 30Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research, Neuherberg, Germany rui.wang-sattler@helmholtz-muenchen.de.

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.

PMID:
26251408
DOI:
10.2337/dc15-0658
[PubMed - indexed for MEDLINE]
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