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Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice.
Int. J. Biol. Macromol. 265:130962 (2024)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Branched-chain Amino Acids ; Diabetic Ketoacidosis ; Lactic Acidosis ; Metformin Adds To Sglt2i ; Sglt2i Monotherapy; Glycogen-synthase Kinase-3; Cotransporter 2 Inhibitor; Type-2 Diabetes-mellitus; Ketone-bodies; Lactic-acidosis; Kidney-disease; Glucose; Protection; Benefits; Mass
ISSN (print) / ISBN
0141-8130
e-ISSN
1879-0003
Quellenangaben
Volume: 265,
Issue: Pt 1,
Article Number: 130962
Publisher
Elsevier
Publishing Place
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Translational Genomics (ITG)
Institute of Epidemiology II (EPI2)
Institute of Experimental Genetics (IEG)
Institute of Epidemiology II (EPI2)
Institute of Experimental Genetics (IEG)
Grants
German Federal Ministry of Health (Berlin, Germany)
EFPIA
European Union
Innovative Medicines Initiative 2 Joint Undertaking (JU)
Uehara Memorial Foundation
EFPIA
European Union
Innovative Medicines Initiative 2 Joint Undertaking (JU)
Uehara Memorial Foundation