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Harada, M. ; Adam, J. ; Han, S. ; Shi, M. ; Ge, J. ; Lintelmann, J. ; Cecil, A. ; Zukunft, S. ; Prehn, C. ; Witting, M. ; Scheerer, M.F. ; Neschen, S. ; Irmler, M. ; Beckers, J. ; Adamski, J. ; Teupser, D.* ; Linkohr, B. ; Gieger, C. ; Hrabě de Angelis, M. ; Peters, A. ; Wang-Sattler, R.

Urea cycle modulation by combined SGLT2 inhibitors and metformin.

BMC Med. 24:55 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i), when combined with metformin (COMBI), offer multi-organ protective effects in patients with type 2 diabetes (T2D), particularly those at high risk of cardiovascular or renal complications. However, the underlying molecular mechanisms remain poorly understood. METHODS: We profiled 303 targeted serum metabolites in 1494 participants of the KORA study, including T2D patients treated with COMBI therapy, metformin monotherapy, or no glucose-lowering medication. Additionally, metabolomic profiling was quantified on seven tissues (plasma, liver, adrenal glands, adipose tissue, testis, lung, and cerebellum), and related hepatic transcripts were evaluated in 40 mice. Multivariable linear regression analyses, adjusted for age, sex, BMI, lifestyle, glycemic, and cardiovascular risk factors, were applied to human data; tissue-specific regression analyses were conducted for murine samples. Identified metabolites were further investigated using biochemical pathway analyses and literature review. RESULTS: COMBI therapy was associated with significant changes in metabolite profiles. In humans, 10 metabolites were significantly altered compared to metformin monotherapy. In mice, 82 altered metabolites were identified in plasma, 52 in liver, 30 in adrenal glands, 12 in adipose tissue, seven in testis, seven in lung, and six in cerebellum. COMBI therapy lowered threonine concentrations in both human serum and murine plasma but raised threonine, glycine, and urea cycle metabolites (citrulline, asymmetric dimethyl arginine (ADMA), and ornithine) in murine liver. This was accompanied by enhanced hepatic expression of Slc38a2, a threonine transporter gene. In humans, urea cycle metabolites correlated strongly with the fibrosis-4 index, a marker of liver fibrosis. Additionally, COMBI therapy elevated ketone body markers, such as hydroxybutyrylcarnitine, across murine liver, plasma, adrenal glands, adipose tissue, and testis. CONCLUSIONS: COMBI therapy modulates amino acid metabolism, the urea cycle, and ketone body production, suggesting potential mechanisms underlying its protective effects against liver fibrosis and male subfertility. These findings provide novel insights into the systemic metabolic actions of COMBI therapy and highlight its translational potential to improve clinical outcomes in T2D patients.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fibrosis-4 Index ; Hydroxybutyrylcarnitine (c4-oh) ; Liver Fibrosis ; Male Subfertility ; Metabolic Dysfunction-associated Steatotic Liver Disease (masld) ; Metformin ; Sodium-glucose Co-transporter 2 Inhibitors (sglt2i) ; Threonine ; Type 2 Diabetes ; Urea Cycle; Glucose; Mice
ISSN (print) / ISBN 1741-7015
e-ISSN 1741-7015
Journal BMC Medicine
Quellenangaben Volume: 24, Issue: 1, Pages: , Article Number: 55 Supplement: ,
Publisher Springer
Publishing Place Campus, 4 Crinan St, London N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
Institute of Epidemiology (EPI)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Experimental Genetics (IEG)
Grants Bavarian State Ministry of Health, Care and Prevention
German Federal Ministry of Education and Research
Uehara Memorial Foundation
Innovative Medicines Initiative 2
German Federal Ministry of Education and Research (BMBF)
Helmholtz Zentrum Mnchen - Deutsches Forschungszentrum fr Gesundheit und Umwelt (GmbH) (4209)