Metabolic Communication by SGLT2 Inhibition
Authors' conclusion
SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.
Study context
- Population
- Nondiabetic and diabetic mice with early, uncomplicated hyperglycemia; human stool microbiota, patients with decompensated HF or DM, human iPSC-derived engineered heart tissue
- Comparison
- SGLT2i vs no SGLT2i
Methodological detailsproteomics, phosphoproteomics and metabolomics, multiple metabolic organs and body fluids
- Proteomics, phosphoproteomics and metabolomics
- Multiple metabolic organs and body fluids
Main finding
As reported in the abstract
1 week
- Kidneys of nondiabetic mice reacted most strongly: less early proximal tubule glucotoxicity, broad downregulation of apical uptake transporters (sodium, glucose, urate, purine bases, amino acids)
- Heart and liver signaling affected; white adipose tissue showed more lipolysis
- Gut microbiome: lower relative abundance of taxa fermenting phenylalanine and tryptophan to CV uremic toxins, with lower plasma levels (incl. p-cresol sulfate)
- SGLT2i detectable in murine stool; addition to human stool microbiota fermentation recapitulated some murine findings
- SGLT2i reduced circulating p-cresol sulfate in SGLT2-lacking mice and in patients with decompensated HF or DM
- P-cresol impaired contractility and rhythm in human iPSC-derived engineered heart tissue
Original publication
Metabolic Communication by SGLT2 Inhibition. Circulation. Published 28 December 2023. doi:10.
Summarised from the published abstract; every number is checked against it