Metabolic Communication by SGLT2 Inhibition

Anja M Billing; Young Chul Kim; Søren Gullaksen; Benedikt Schrage; Janice Raabe; Arvid Hutzfeldt; Fatih Demir; Elina Kovalenko; Moritz Lassé; Aurelien Dugourd; Robin Fallegger; Birgit Klampe; Johannes Jaegers; Qing Li; Olha Kravtsova; Maria Crespo-Masip; Amelia Palermo; Robert A Fenton; Elion Hoxha; Stefan Blankenberg; Paulus Kirchhof; Tobias B Huber; Esben Laugesen; Tanja Zeller; Maria Chrysopolou; Julio Saez-Rodriguez; Christina Magnussen; Thomas Eschenhagen; Alexander Staruschenko; Gary Siuzdak; Per L Poulsen; Clarissa Schwab; Friederike Cuello; Volker Vallon; Markus M Rinschen

doi:10.1161/CIRCULATIONAHA.123.065517

Metabolic Communication by SGLT2 Inhibition

Anja M Billing, Young Chul Kim, Søren Gullaksen, Benedikt Schrage, Janice Raabe, Arvid Hutzfeldt, Fatih Demir, Elina Kovalenko, Moritz Lassé, Aurelien Dugourd, Robin Fallegger, Birgit Klampe, Johannes Jaegers, Qing Li, Olha Kravtsova, Maria Crespo-Masip, Amelia Palermo, Robert A Fenton, Elion Hoxha, Stefan BlankenbergPaulus Kirchhof, Tobias B Huber, Esben Laugesen, Tanja Zeller, Maria Chrysopolou, Julio Saez-Rodriguez, Christina Magnussen, Thomas Eschenhagen, Alexander Staruschenko, Gary Siuzdak, Per L Poulsen, Clarissa Schwab, Friederike Cuello, Volker Vallon, Markus M Rinschen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

38 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Circulation
Volume	149
Issue	11
Pages (from-to)	860-884
Number of pages	25
ISSN	0009-7322
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.123.065517
Publication status	Published - Mar 2024

Keywords

diabetes mellitus
gastrointestinal microbiome
heart
kidney
metabolome
plasma
proteome
sodium-glucose transporter 2 inhibitors
uremic toxins
urine
Humans
Sodium/metabolism
Glucose
Diabetes Mellitus, Experimental/drug therapy
Cresols
Sodium-Glucose Transporter 2/metabolism
Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Uremic Toxins
Tryptophan
Diabetes Mellitus, Type 2/complications
Sulfuric Acid Esters
Animals
Proteomics
Uric Acid
Induced Pluripotent Stem Cells/metabolism
Mice

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Billing, A. M., Kim, Y. C., Gullaksen, S., Schrage, B., Raabe, J., Hutzfeldt, A., Demir, F., Kovalenko, E., Lassé, M., Dugourd, A., Fallegger, R., Klampe, B., Jaegers, J., Li, Q., Kravtsova, O., Crespo-Masip, M., Palermo, A., Fenton, R. A., Hoxha, E., ... Rinschen, M. M. (2024). Metabolic Communication by SGLT2 Inhibition. Circulation, 149(11), 860-884. https://doi.org/10.1161/CIRCULATIONAHA.123.065517

@article{fe6488bf647049f3a5b50dc7c5664b06,

title = "Metabolic Communication by SGLT2 Inhibition",

abstract = "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.",

keywords = "diabetes mellitus, gastrointestinal microbiome, heart, kidney, metabolome, plasma, proteome, sodium-glucose transporter 2 inhibitors, uremic toxins, urine, Humans, Sodium/metabolism, Glucose, Diabetes Mellitus, Experimental/drug therapy, Cresols, Sodium-Glucose Transporter 2/metabolism, Sodium-Glucose Transporter 2 Inhibitors/pharmacology, Uremic Toxins, Tryptophan, Diabetes Mellitus, Type 2/complications, Sulfuric Acid Esters, Animals, Proteomics, Uric Acid, Induced Pluripotent Stem Cells/metabolism, Mice",

author = "Billing, {Anja M} and Kim, {Young Chul} and S{\o}ren Gullaksen and Benedikt Schrage and Janice Raabe and Arvid Hutzfeldt and Fatih Demir and Elina Kovalenko and Moritz Lass{\'e} and Aurelien Dugourd and Robin Fallegger and Birgit Klampe and Johannes Jaegers and Qing Li and Olha Kravtsova and Maria Crespo-Masip and Amelia Palermo and Fenton, {Robert A} and Elion Hoxha and Stefan Blankenberg and Paulus Kirchhof and Huber, {Tobias B} and Esben Laugesen and Tanja Zeller and Maria Chrysopolou and Julio Saez-Rodriguez and Christina Magnussen and Thomas Eschenhagen and Alexander Staruschenko and Gary Siuzdak and Poulsen, {Per L} and Clarissa Schwab and Friederike Cuello and Volker Vallon and Rinschen, {Markus M}",

year = "2024",

month = mar,

doi = "10.1161/CIRCULATIONAHA.123.065517",

language = "English",

volume = "149",

pages = "860--884",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "11",

}

Billing, AM, Kim, YC, Gullaksen, S, Schrage, B, Raabe, J, Hutzfeldt, A, Demir, F , Kovalenko, E, Lassé, M, Dugourd, A, Fallegger, R, Klampe, B, Jaegers, J, Li, Q, Kravtsova, O, Crespo-Masip, M, Palermo, A, Fenton, RA, Hoxha, E, Blankenberg, S, Kirchhof, P, Huber, TB, Laugesen, E, Zeller, T, Chrysopolou, M, Saez-Rodriguez, J, Magnussen, C, Eschenhagen, T, Staruschenko, A, Siuzdak, G, Poulsen, PL , Schwab, C, Cuello, F, Vallon, V & Rinschen, MM 2024, 'Metabolic Communication by SGLT2 Inhibition', Circulation, vol. 149, no. 11, pp. 860-884. https://doi.org/10.1161/CIRCULATIONAHA.123.065517

TY - JOUR

T1 - Metabolic Communication by SGLT2 Inhibition

AU - Billing, Anja M

AU - Kim, Young Chul

AU - Gullaksen, Søren

AU - Schrage, Benedikt

AU - Raabe, Janice

AU - Hutzfeldt, Arvid

AU - Demir, Fatih

AU - Kovalenko, Elina

AU - Lassé, Moritz

AU - Dugourd, Aurelien

AU - Fallegger, Robin

AU - Klampe, Birgit

AU - Jaegers, Johannes

AU - Li, Qing

AU - Kravtsova, Olha

AU - Crespo-Masip, Maria

AU - Palermo, Amelia

AU - Fenton, Robert A

AU - Hoxha, Elion

AU - Blankenberg, Stefan

AU - Kirchhof, Paulus

AU - Huber, Tobias B

AU - Laugesen, Esben

AU - Zeller, Tanja

AU - Chrysopolou, Maria

AU - Saez-Rodriguez, Julio

AU - Magnussen, Christina

AU - Eschenhagen, Thomas

AU - Staruschenko, Alexander

AU - Siuzdak, Gary

AU - Poulsen, Per L

AU - Schwab, Clarissa

AU - Cuello, Friederike

AU - Vallon, Volker

AU - Rinschen, Markus M

PY - 2024/3

Y1 - 2024/3

N2 - 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.

AB - 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.

KW - diabetes mellitus

KW - gastrointestinal microbiome

KW - heart

KW - kidney

KW - metabolome

KW - plasma

KW - proteome

KW - sodium-glucose transporter 2 inhibitors

KW - uremic toxins

KW - urine

KW - Humans

KW - Sodium/metabolism

KW - Glucose

KW - Diabetes Mellitus, Experimental/drug therapy

KW - Cresols

KW - Sodium-Glucose Transporter 2/metabolism

KW - Sodium-Glucose Transporter 2 Inhibitors/pharmacology

KW - Uremic Toxins

KW - Tryptophan

KW - Diabetes Mellitus, Type 2/complications

KW - Sulfuric Acid Esters

KW - Animals

KW - Proteomics

KW - Uric Acid

KW - Induced Pluripotent Stem Cells/metabolism

KW - Mice

U2 - 10.1161/CIRCULATIONAHA.123.065517

DO - 10.1161/CIRCULATIONAHA.123.065517

M3 - Journal article

C2 - 38152989

SN - 0009-7322

VL - 149

SP - 860

EP - 884

JO - Circulation

JF - Circulation

IS - 11

ER -

Metabolic Communication by SGLT2 Inhibition

Abstract

Keywords

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