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

Harada, Makoto (author), Adamski, Jerzy (author), Wang-Sattler, Rui (author)

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.

• Language: English
• Keywords: anaplerosis, metabolic dysfunction-associated steatotic liver disease (MASLD), anti-inflammatory effects, metformin, pharmacometabolomics, SGLT2 inhibitors, TCA cycle, type 2 diabetes
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 14 str.
• Numbering: Vol. 23, art. 199
• PID: 20.500.12556/RUL-182278
• UDC: 577:61
• ISSN on article: 1475-2840
• DOI: 10.1186/s12933-024-02288-x
• COBISS.SI-ID: 265262339
• Publication date in RUL: 06.05.2026

Record is a part of a journal

• Title: Cardiovascular diabetology
• Shortened title: Cardiovasc Diabetol
• Publisher: Springer Nature
• ISSN: 1475-2840
• COBISS.SI-ID: 2595092

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• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

• License: CC0 1.0, Creative Commons CC0 1.0 Universal
• Link: https://creativecommons.org/publicdomain/zero/1.0/deed.en
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Secondary language

• Language: Slovenian
• Keywords: anapleroza, steatozna bolezen jeter, povezana s presnovno disfunkcijo, protivnetni učinki, metformin, farmakometabolomika, zaviralci SGLT2, cikel TCA, sladkorna bolezen tipa 2