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Harada, M. ; Adam, J. ; Covic, M. ; Brandmaier, S. ; Muschet, C. ; Huang, J. ; Han, S. ; Rommel, M. ; Rotter, M. ; Heier, M. ; Mohney, R.P.* ; Krumsiek, J. ; Kastenmüller, G. ; Rathmann, W.* ; Zou, Z.* ; Zukunft, S. ; Scheerer, M.F. ; Neschen, S. ; Adamski, J. ; Gieger, C. ; Peters, A. ; Ankerst, D.P.* ; Meitinger, T.* ; Alderete, T.L.* ; Hrabě de Angelis, M. ; Suhre, K.* ; Wang-Sattler, R.

Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i.

Cardiovasc. Diabetol. 23:199 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. METHODS: Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. RESULTS: Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. CONCLUSION: This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Anaplerosis ; Anti-inflammatory Effects ; Metabolic Dysfunction-associated Steatotic Liver Disease (masld) ; Metformin ; Pharmacometabolomics ; Sglt2 Inhibitors ; Tca Cycle ; Type 2 Diabetes; Glucose; Association; Profiles; Taurine; Mice
ISSN (print) / ISBN 1475-2840
e-ISSN 1475-2840
Zeitschrift Cardiovascular Diabetology
Quellenangaben Band: 23, Heft: 1, Seiten: , Artikelnummer: 199 Supplement: ,
Verlag BioMed Central
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
Institute of Epidemiology II (EPI2)
Institute of Experimental Genetics (IEG)
Institute of Computational Biology (ICB)
Förderungen Qatar National Research Fund (QNRF)
German Federal Ministry of Health (Berlin, Germany)
Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitaet, LMUinnovativ
German Federal Ministry of Education and Research (BMBF), State of Bavaria
Helmholtz Zentrum Muenchen- German Research Center for Environmental Health
Helmholtz Portfolio Theme "Metabolic Dysfunction and Disease."
Network Fund of the Helmholtz Association
Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases)
German Federal Ministry of Education and Research to the German Center for Diabetes Research and to the Research Consortium "Systems Biology of Metabotypes"
Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (Dusseldorf, Germany)
German Research Foundation (DFG)
EU FP7
Qatar Foundation
Biomedical Research Program' funds at Weill Cornell Medicine in Qatar
Ministry of Science and Technology of China
European Federation of Pharmaceutical Industries and Associations (EFPIA)
Innovative Medicines Initiative 2 Joint Undertaking (JU)
European Institute of Innovation and Technology (EIT )
DeTecT2D & iPDM-GO EIT Health Innovation
European Union
Projekt DEAL