Details

Autor(en) / Beteiligte

• Harada, Makoto
• Han, Siyu
• Shi, Mengya
• Ge, Jianhong
• Yu, Shixiang
• Adam, Jonathan
• Adamski, Jerzy
• Scheerer, Markus F.
• Neschen, Susanne
• de Angelis, Martin Hrabe
• Wang-Sattler, Rui

Titel

Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice

Ist Teil von

• International journal of biological macromolecules, 2024-04, Vol.265 (Pt 1), p.130962-130962, Article 130962

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment. •SGLT2i monotherapy elevates the ketone body (3HBA), enhancing systemic ketogenesis.•SGLT2i upregulates fatty acid oxidation and protein catabolism metabolites.•Combining SGLT2i with metformin reduces kidney, liver protein breakdown.•SGLT2i + metformin affect GSK3/mTOR1, altering cell growth, metabolism.