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Adam, J. ; Brandmaier, S. ; Leonhardt, J. ; Scheerer, M.F. ; Mohney, R.P.* ; Xu, T. ; Bi, J.* ; Rotter, M. ; Troll, M. ; Chi, S. ; Heier, M. ; Herder, C.* ; Rathmann, W.G.* ; Giani, G.* ; Adamski, J. ; Illig, T.* ; Strauch, K. ; Li, Y.* ; Gieger, C. ; Peters, A. ; Suhre, K. ; Ankerst, D.P.* ; Meitinger, T. ; Hrabě de Angelis, M. ; Roden, M.* ; Neschen, S. ; Kastenmüller, G. ; Wang-Sattler, R.

Metformin effect on non-targeted metabolite profiles in patients with type 2 diabetes and multiple murine tissues.

Diabetes 65, 3776-3785 (2016)

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Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim is to investigate metformin's pleiotropic effect using a non-targeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA F4 cohort. To compare T2D patients treated with metformin (mt-T2D, n=74) and those without antidiabetic medication (ndt-T2D, n=115), we used multivariable linear regression models in a cross-sectional study. We applied 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 values 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 seven years' 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 non-targeted approach, most likely result from metformin's pleiotropic effect on the interlocked urea and nitric oxide cycle. The translational data derived from of multiple murine tissues corroborated and complemented the findings from the human cohort.

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