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Metabolic communication by SGLT2 inhibition

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. - METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improve...

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Main Authors: Billing, Anja M. (Author) , Kim, Young Chul (Author) , Gullaksen, Søren (Author) , Schrage, Benedikt (Author) , Raabe, Janice (Author) , Hutzfeldt, Arvid (Author) , Demir, Fatih (Author) , Kovalenko, Elina (Author) , Lassé, Moritz (Author) , Dugourd, Aurelien (Author) , Fallegger, Robin (Author) , Klampe, Birgit (Author) , Jaegers, Johannes (Author) , Li, Qing (Author) , Kravtsova, Olha (Author) , Crespo-Masip, Maria (Author) , Palermo, Amelia (Author) , Fenton, Robert A. (Author) , Hoxha, Elion (Author) , Blankenberg, Stefan (Author) , Kirchhof, Paulus (Author) , Huber, Tobias B. (Author) , Laugesen, Esben (Author) , Zeller, Tanja (Author) , Chrysopoulou, Maria (Author) , Sáez Rodríguez, Julio (Author) , Magnussen, Christina (Author) , Eschenhagen, Thomas (Author) , Staruschenko, Alexander (Author) , Siuzdak, Gary (Author) , Poulsen, Per L. (Author) , Schwab, Clarissa (Author) , Cuello, Friederike (Author) , Vallon, Volker (Author) , Rinschen, Markus M. (Author)
Format: Article (Journal)
Language:English
Published: 2024
In: Circulation
Year: 2024, Volume: 149, Issue: 11, Pages: 860-884
ISSN:1524-4539
DOI:10.1161/CIRCULATIONAHA.123.065517
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1161/CIRCULATIONAHA.123.065517
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Author Notes:Anja M. Billing, PhD, Young Chul Kim, PhD, Søren Gullaksen, MD, Benedikt Schrage, MD, PhD, Janice Raabe, PhD, Arvid Hutzfeldt, MSc, Fatih Demir, PhD, Elina Kovalenko, MSc, Moritz Lassé, PhD, Aurelien Dugourd, PhD, Robin Fallegger, MSc, Birgit Klampe, Johannes Jaegers, PhD, Qing Li, PhD, Olha Kravtsova, PhD, Maria Crespo-Masip, PhD, Amelia Palermo, PhD, Robert A. Fenton, PhD, Elion Hoxha, MD, Stefan Blankenberg, MD, Paulus Kirchhof, MD, Tobias B. Huber, MD, Esben Laugesen, MD, Tanja Zeller, PhD, Maria Chrysopoulou, MSc, Julio Saez-Rodriguez, PhD, Christina Magnussen, Thomas Eschenhagen, MD, Alexander Staruschenko, PhD, Gary Siuzdak, PhD, Per L. Poulsen, MD, Clarissa Schwab, PhD, Friederike Cuello, PhD, Volker Vallon, MD, and Markus M. Rinschen, MD

MARC

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245 1 0 |a Metabolic communication by SGLT2 inhibition  |c Anja M. Billing, PhD, Young Chul Kim, PhD, Søren Gullaksen, MD, Benedikt Schrage, MD, PhD, Janice Raabe, PhD, Arvid Hutzfeldt, MSc, Fatih Demir, PhD, Elina Kovalenko, MSc, Moritz Lassé, PhD, Aurelien Dugourd, PhD, Robin Fallegger, MSc, Birgit Klampe, Johannes Jaegers, PhD, Qing Li, PhD, Olha Kravtsova, PhD, Maria Crespo-Masip, PhD, Amelia Palermo, PhD, Robert A. Fenton, PhD, Elion Hoxha, MD, Stefan Blankenberg, MD, Paulus Kirchhof, MD, Tobias B. Huber, MD, Esben Laugesen, MD, Tanja Zeller, PhD, Maria Chrysopoulou, MSc, Julio Saez-Rodriguez, PhD, Christina Magnussen, Thomas Eschenhagen, MD, Alexander Staruschenko, PhD, Gary Siuzdak, PhD, Per L. Poulsen, MD, Clarissa Schwab, PhD, Friederike Cuello, PhD, Volker Vallon, MD, and Markus M. Rinschen, MD 
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520 |a BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. - METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia. - RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell-derived engineered heart tissue. - CONCLUSIONS: 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. 
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650 4 |a Cresols 
650 4 |a diabetes mellitus 
650 4 |a Diabetes Mellitus, Experimental 
650 4 |a Diabetes Mellitus, Type 2 
650 4 |a gastrointestinal microbiome 
650 4 |a Glucose 
650 4 |a heart 
650 4 |a Humans 
650 4 |a Induced Pluripotent Stem Cells 
650 4 |a kidney 
650 4 |a metabolome 
650 4 |a Mice 
650 4 |a plasma 
650 4 |a proteome 
650 4 |a Proteomics 
650 4 |a Sodium 
650 4 |a Sodium-Glucose Transporter 2 
650 4 |a sodium-glucose transporter 2 inhibitors 
650 4 |a Sodium-Glucose Transporter 2 Inhibitors 
650 4 |a Sulfuric Acid Esters 
650 4 |a Tryptophan 
650 4 |a uremic toxins 
650 4 |a Uremic Toxins 
650 4 |a Uric Acid 
650 4 |a urine 
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