Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

T Xu; S Brandmaier; AC Messias; Cindy Herder; HHM Draisma; Ayse Demirkan; ZH Yu; JS Ried; T Haller; M Heier; M Campillos; G Fobo; R Stark; C Holzapfel; J Adam; S Chi; M Rotter; T Panni; AS Quante; Y He; C Prehn; W Roemisch-Margl; G Kastenmuller; G Willemsen; R Pool; K Kasa; KW van Dijk; T Hankemeier; C Meisinger; B Thorand; A Ruepp; MH de Angelis; YX Li; HE Wichmann; B Stratmann; K Strauch; A Metspalu; C Gieger; K Suhre; J Adamski; T Illig; W Rathmann; M Roden; A Peters; Cornelia Duijn; DI Boomsma; T Meitinger; R Wang-Sattler

doi:10.2337/dc15-0658

Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

T Xu, S Brandmaier, AC Messias, Cindy Herder, HHM Draisma, Ayse Demirkan, ZH Yu, JS Ried, T Haller, M Heier, M Campillos, G Fobo, R Stark, C Holzapfel, J Adam, S Chi, M Rotter, T Panni, AS Quante, Y HeC Prehn, W Roemisch-Margl, G Kastenmuller, G Willemsen, R Pool, K Kasa, KW van Dijk, T Hankemeier, C Meisinger, B Thorand, A Ruepp, MH de Angelis, YX Li, HE Wichmann, B Stratmann, K Strauch, A Metspalu, C Gieger, K Suhre, J Adamski, T Illig, W Rathmann, M Roden, A Peters, Cornelia Duijn, DI Boomsma, T Meitinger, R Wang-Sattler

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

OBJECTIVEMetformin 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 METHODSWe 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.RESULTSWe 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.CONCLUSIONSOur 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 language	Undefined/Unknown
Pages (from-to)	1858-1867
Number of pages	10
Journal	Diabetes Care
Volume	38
Issue number	10
DOIs	https://doi.org/10.2337/dc15-0658
Publication status	Published - 2015

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Cite this

Xu, T., Brandmaier, S., Messias, AC., Herder, C., Draisma, HHM., Demirkan, A., Yu, ZH., Ried, JS., Haller, T., Heier, M., Campillos, M., Fobo, G., Stark, R., Holzapfel, C., Adam, J., Chi, S., Rotter, M., Panni, T., Quante, AS., ... 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

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title = "Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes",

abstract = "OBJECTIVEMetformin 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 METHODSWe 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.RESULTSWe 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.CONCLUSIONSOur 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.",

author = "T Xu and S Brandmaier and AC Messias and Cindy Herder and HHM Draisma and Ayse Demirkan and ZH Yu and JS Ried and T Haller and M Heier and M Campillos and G Fobo and R Stark and C Holzapfel and J Adam and S Chi and M Rotter and T Panni and AS Quante and Y He and C Prehn and W Roemisch-Margl and G Kastenmuller and G Willemsen and R Pool and K Kasa and {van Dijk}, KW and T Hankemeier and C Meisinger and B Thorand and A Ruepp and {de Angelis}, MH and YX Li and HE Wichmann and B Stratmann and K Strauch and A Metspalu and C Gieger and K Suhre and J Adamski and T Illig and W Rathmann and M Roden and A Peters and Cornelia Duijn and DI Boomsma and T Meitinger and R Wang-Sattler",

year = "2015",

doi = "10.2337/dc15-0658",

language = "Undefined/Unknown",

volume = "38",

pages = "1858--1867",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "10",

}

Xu, T, Brandmaier, S, Messias, AC, Herder, C, Draisma, HHM, Demirkan, A, Yu, ZH, 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, YX, Wichmann, HE, Stratmann, B, Strauch, K, Metspalu, A, Gieger, C, Suhre, K, Adamski, J, Illig, T, Rathmann, W, Roden, M, Peters, A, Duijn, C, 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

TY - JOUR

T1 - Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

AU - Xu, T

AU - Brandmaier, S

AU - Messias, AC

AU - Herder, Cindy

AU - Draisma, HHM

AU - Demirkan, Ayse

AU - Yu, ZH

AU - Ried, JS

AU - Haller, T

AU - Heier, M

AU - Campillos, M

AU - Fobo, G

AU - Stark, R

AU - Holzapfel, C

AU - Adam, J

AU - Chi, S

AU - Rotter, M

AU - Panni, T

AU - Quante, AS

AU - He, Y

AU - Prehn, C

AU - Roemisch-Margl, W

AU - Kastenmuller, G

AU - Willemsen, G

AU - Pool, R

AU - Kasa, K

AU - van Dijk, KW

AU - Hankemeier, T

AU - Meisinger, C

AU - Thorand, B

AU - Ruepp, A

AU - de Angelis, MH

AU - Li, YX

AU - Wichmann, HE

AU - Stratmann, B

AU - Strauch, K

AU - Metspalu, A

AU - Gieger, C

AU - Suhre, K

AU - Adamski, J

AU - Illig, T

AU - Rathmann, W

AU - Roden, M

AU - Peters, A

AU - Duijn, Cornelia

AU - Boomsma, DI

AU - Meitinger, T

AU - Wang-Sattler, R

PY - 2015

Y1 - 2015

N2 - OBJECTIVEMetformin 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 METHODSWe 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.RESULTSWe 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.CONCLUSIONSOur 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 - OBJECTIVEMetformin 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 METHODSWe 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.RESULTSWe 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.CONCLUSIONSOur 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.

U2 - 10.2337/dc15-0658

DO - 10.2337/dc15-0658

M3 - Article

C2 - 26251408

SN - 0149-5992

VL - 38

SP - 1858

EP - 1867

JO - Diabetes Care

JF - Diabetes Care

IS - 10

ER -