Abstract
Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (NDT-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-Treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with NDT-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-Treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived frommultiplemurine tissues corroborated and complemented the findings from the human cohort.
| Original language | English |
|---|---|
| Pages (from-to) | 3776-3785 |
| Number of pages | 10 |
| Journal | Diabetes |
| Volume | 65 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 1 Dec 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Metformin effect on nontargeted metabolite profiles in patients with type 2 diabetes and in multiple murine tissues. / Rui, Wang Sattler; Adam, Jonathan; Brandmaier, Stefan; Leonhardt, Jörn; Scheerer, Markus F.; Mohney, Robert P.; Xu, Tao; Bi, Jie; Rotter, Markus; Troll, Martina; Chi, Shen; Heier, Margit; Herder, Christian; Rathmann, Wolfgang; Giani, Guido; Adamski, Jerzy; Illig, Thomas; Strauch, Konstantin; Li, Yixue; Gieger, Christian; Peters, Annette; Suhre, Karsten; Ankerst, Donna; Meitinger, Thomas; De Angelis, Martin Hrabě; Roden, Michael; Neschen, Susanne; Kastenmüller, Gabi.
In: Diabetes, Vol. 65, No. 12, 01.12.2016, p. 3776-3785.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Metformin effect on nontargeted metabolite profiles in patients with type 2 diabetes and in multiple murine tissues
AU - Rui, Wang Sattler
AU - Adam, Jonathan
AU - Brandmaier, Stefan
AU - Leonhardt, Jörn
AU - Scheerer, Markus F.
AU - Mohney, Robert P.
AU - Xu, Tao
AU - Bi, Jie
AU - Rotter, Markus
AU - Troll, Martina
AU - Chi, Shen
AU - Heier, Margit
AU - Herder, Christian
AU - Rathmann, Wolfgang
AU - Giani, Guido
AU - Adamski, Jerzy
AU - Illig, Thomas
AU - Strauch, Konstantin
AU - Li, Yixue
AU - Gieger, Christian
AU - Peters, Annette
AU - Suhre, Karsten
AU - Ankerst, Donna
AU - Meitinger, Thomas
AU - De Angelis, Martin Hrabě
AU - Roden, Michael
AU - Neschen, Susanne
AU - Kastenmüller, Gabi
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (NDT-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-Treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with NDT-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-Treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived frommultiplemurine tissues corroborated and complemented the findings from the human cohort.
AB - Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (NDT-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-Treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with NDT-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-Treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived frommultiplemurine tissues corroborated and complemented the findings from the human cohort.
UR - http://www.scopus.com/inward/record.url?scp=85000789398&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85000789398&partnerID=8YFLogxK
U2 - 10.2337/db16-0512
DO - 10.2337/db16-0512
M3 - Article
VL - 65
SP - 3776
EP - 3785
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -