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 & 28 others Cornelia Prehn, Werner Roemisch-Margl, Gabi Kastenmuller, Gonneke Willemsen, Reńe Pool, Katarina Kasa, Ko Willems Van Dijk, Thomas Hankemeier, Christa Meisinger, Barbara Thorand, Andreas Ruepp, Martin Hrabe De Angelis, Yixue Li, H. E. 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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 131metabolites in fasting serumsamples and usedmultivariable 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 metforminassociated 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 groupswhowere not using glucose-lowering oralmedication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of thesemetabolites 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.

Original languageEnglish
Pages (from-to)1858-1867
Number of pages10
JournalDiabetes Care
Volume38
Issue number10
DOIs
Publication statusPublished - 1 Oct 2015
Externally publishedYes

Fingerprint

Metformin
LDL Cholesterol
Type 2 Diabetes Mellitus
AMP-Activated Protein Kinases
Phosphatidylcholines
Linear Models
low density lipoprotein inhibitor
Metagenomics
Metabolomics
Longitudinal Studies
Fasting
Cardiovascular Diseases
Therapeutics
Cross-Sectional Studies
Lipids
Glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing

Cite this

Xu, T., Brandmaier, S., Messias, A. C., Herder, C., Draisma, H. H. M., Demirkan, A., ... Wang-Sattler, R. (2015). Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care, 38(10), 1858-1867. https://doi.org/10.2337/dc15-0658

Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. / Xu, Tao; Brandmaier, Stefan; Messias, Ana C.; Herder, Christian; Draisma, Harmen H M; Demirkan, Ayse; Yu, Zhonghao; Ried, Janina S.; Haller, Toomas; Heier, Margit; Campillos, Monica; Fobo, Gisela; Stark, Renee; Holzapfel, Christina; Adam, Jonathan; Chi, Shen; Rotter, Markus; Panni, Tommaso; Quante, Anne S.; He, Ying; Prehn, Cornelia; Roemisch-Margl, Werner; Kastenmuller, Gabi; Willemsen, Gonneke; Pool, Reńe; Kasa, Katarina; Van Dijk, Ko Willems; Hankemeier, Thomas; Meisinger, Christa; Thorand, Barbara; Ruepp, Andreas; De Angelis, Martin Hrabe; Li, Yixue; Wichmann, H. E.; Stratmann, Bernd; Strauch, Konstantin; Metspalu, Andres; Gieger, Christian; Suhre, Karsten; Adamski, Jerzy; Illig, Thomas; Rathmann, Wolfgang; Roden, Michael; Peters, Annette; Van Duijn, Cornelia M.; Boomsma, Dorret I.; Meitinger, Thomas; Wang-Sattler, Rui.

In: Diabetes Care, Vol. 38, No. 10, 01.10.2015, p. 1858-1867.

Research output: Contribution to journalArticle

Xu, T, Brandmaier, S, Messias, AC, Herder, C, Draisma, HHM, Demirkan, A, Yu, Z, Ried, JS, Haller, T, Heier, M, Campillos, M, Fobo, G, Stark, R, Holzapfel, C, Adam, J, Chi, S, Rotter, M, Panni, T, Quante, AS, He, Y, Prehn, C, Roemisch-Margl, W, Kastenmuller, G, Willemsen, G, Pool, R, Kasa, K, Van Dijk, KW, Hankemeier, T, Meisinger, C, Thorand, B, Ruepp, A, De Angelis, MH, Li, Y, Wichmann, HE, Stratmann, B, Strauch, K, Metspalu, A, Gieger, C, Suhre, K, Adamski, J, Illig, T, Rathmann, W, Roden, M, Peters, A, Van Duijn, CM, Boomsma, DI, Meitinger, T & Wang-Sattler, R 2015, 'Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes', Diabetes Care, vol. 38, no. 10, pp. 1858-1867. https://doi.org/10.2337/dc15-0658
Xu T, Brandmaier S, Messias AC, Herder C, Draisma HHM, Demirkan A et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care. 2015 Oct 1;38(10):1858-1867. https://doi.org/10.2337/dc15-0658
Xu, Tao ; Brandmaier, Stefan ; Messias, Ana C. ; Herder, Christian ; Draisma, Harmen H M ; Demirkan, Ayse ; Yu, Zhonghao ; Ried, Janina S. ; Haller, Toomas ; Heier, Margit ; Campillos, Monica ; Fobo, Gisela ; Stark, Renee ; Holzapfel, Christina ; Adam, Jonathan ; Chi, Shen ; Rotter, Markus ; Panni, Tommaso ; Quante, Anne S. ; He, Ying ; Prehn, Cornelia ; Roemisch-Margl, Werner ; Kastenmuller, Gabi ; Willemsen, Gonneke ; Pool, Reńe ; Kasa, Katarina ; Van Dijk, Ko Willems ; Hankemeier, Thomas ; Meisinger, Christa ; Thorand, Barbara ; Ruepp, Andreas ; De Angelis, Martin Hrabe ; Li, Yixue ; Wichmann, H. E. ; Stratmann, Bernd ; Strauch, Konstantin ; Metspalu, Andres ; Gieger, Christian ; Suhre, Karsten ; Adamski, Jerzy ; Illig, Thomas ; Rathmann, Wolfgang ; Roden, Michael ; Peters, Annette ; Van Duijn, Cornelia M. ; Boomsma, Dorret I. ; Meitinger, Thomas ; Wang-Sattler, Rui. / Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. In: Diabetes Care. 2015 ; Vol. 38, No. 10. pp. 1858-1867.
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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 131metabolites in fasting serumsamples and usedmultivariable 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 metforminassociated 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 groupswhowere not using glucose-lowering oralmedication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of thesemetabolites 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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T1 - Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes

AU - Xu, Tao

AU - Brandmaier, Stefan

AU - Messias, Ana C.

AU - Herder, Christian

AU - Draisma, Harmen H M

AU - Demirkan, Ayse

AU - Yu, Zhonghao

AU - Ried, Janina S.

AU - Haller, Toomas

AU - Heier, Margit

AU - Campillos, Monica

AU - Fobo, Gisela

AU - Stark, Renee

AU - Holzapfel, Christina

AU - Adam, Jonathan

AU - Chi, Shen

AU - Rotter, Markus

AU - Panni, Tommaso

AU - Quante, Anne S.

AU - He, Ying

AU - Prehn, Cornelia

AU - Roemisch-Margl, Werner

AU - Kastenmuller, Gabi

AU - Willemsen, Gonneke

AU - Pool, Reńe

AU - Kasa, Katarina

AU - Van Dijk, Ko Willems

AU - Hankemeier, Thomas

AU - Meisinger, Christa

AU - Thorand, Barbara

AU - Ruepp, Andreas

AU - De Angelis, Martin Hrabe

AU - Li, Yixue

AU - Wichmann, H. E.

AU - Stratmann, Bernd

AU - Strauch, Konstantin

AU - Metspalu, Andres

AU - Gieger, Christian

AU - Suhre, Karsten

AU - Adamski, Jerzy

AU - Illig, Thomas

AU - Rathmann, Wolfgang

AU - Roden, Michael

AU - Peters, Annette

AU - Van Duijn, Cornelia M.

AU - Boomsma, Dorret I.

AU - Meitinger, Thomas

AU - Wang-Sattler, Rui

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N2 - 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 131metabolites in fasting serumsamples and usedmultivariable 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 metforminassociated 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 groupswhowere not using glucose-lowering oralmedication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of thesemetabolites 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.

AB - 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 131metabolites in fasting serumsamples and usedmultivariable 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 metforminassociated 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 groupswhowere not using glucose-lowering oralmedication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of thesemetabolites 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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