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Metabolic Communication by SGLT2 Inhibition.
Billing, Anja M; Kim, Young Chul; Gullaksen, Søren; Schrage, Benedikt; Raabe, Janice; Hutzfeldt, Arvid; Demir, Fatih; Kovalenko, Elina; Lassé, Moritz; Dugourd, Aurelien; Fallegger, Robin; Klampe, Birgit; Jaegers, Johannes; Li, Qing; Kravtsova, Olha; Crespo-Masip, Maria; Palermo, Amelia; Fenton, Robert A; Hoxha, Elion; Blankenberg, Stefan; Kirchhof, Paulus; Huber, Tobias B; Laugesen, Esben; Zeller, Tanja; Chrysopoulou, Maria; Saez-Rodriguez, Julio; Magnussen, Christina; Eschenhagen, Thomas; Staruschenko, Alexander; Siuzdak, Gary; Poulsen, Per L; Schwab, Clarissa; Cuello, Friederike; Vallon, Volker; Rinschen, Markus M.
Afiliación
  • Billing AM; Departments of Biomedicine (A.M.B., F.D., E.K., J.J., R.A.F., M.C., M.M.R.), Aarhus University, Denmark.
  • Kim YC; Departments of Medicine and Pharmacology, University of California San Diego, La Jolla (Y.C.K., M.C.-M., V.V.).
  • Gullaksen S; VA San Diego Healthcare System, CA (Y.C.K., M.C.-M., V.V.).
  • Schrage B; Clinical Medicine (S.G., P.L.P.), Aarhus University, Denmark.
  • Raabe J; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark (S.G., E.L.).
  • Hutzfeldt A; Department of Cardiology, University Heart and Vascular Center Hamburg, Germany (B.S., S.B., P.K., T.Z., C.M.).
  • Demir F; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany (B.S., J.R., S.B., P.K., T.Z., C.M., T.E., F.C.).
  • Kovalenko E; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany (B.S., J.R., S.B., P.K., T.Z., C.M., T.E., F.C.).
  • Lassé M; Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.R., B.K., T.E., F.C.).
  • Dugourd A; III Department of Medicine and Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.H., M.L., E.H., T.B.H., M.M.R.).
  • Fallegger R; Departments of Biomedicine (A.M.B., F.D., E.K., J.J., R.A.F., M.C., M.M.R.), Aarhus University, Denmark.
  • Klampe B; Departments of Biomedicine (A.M.B., F.D., E.K., J.J., R.A.F., M.C., M.M.R.), Aarhus University, Denmark.
  • Jaegers J; III Department of Medicine and Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.H., M.L., E.H., T.B.H., M.M.R.).
  • Li Q; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, BioQuant, Heidelberg, Germany (A.D., R.F., J.S.-R.).
  • Kravtsova O; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, BioQuant, Heidelberg, Germany (A.D., R.F., J.S.-R.).
  • Crespo-Masip M; Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.R., B.K., T.E., F.C.).
  • Palermo A; Departments of Biomedicine (A.M.B., F.D., E.K., J.J., R.A.F., M.C., M.M.R.), Aarhus University, Denmark.
  • Fenton RA; Engineering (Q.L., C.S.), Aarhus University, Denmark.
  • Hoxha E; Departments of Biomedicine (A.M.B., F.D., E.K., J.J., R.A.F., M.C., M.M.R.), Aarhus University, Denmark.
  • Blankenberg S; Departments of Medicine and Pharmacology, University of California San Diego, La Jolla (Y.C.K., M.C.-M., V.V.).
  • Kirchhof P; VA San Diego Healthcare System, CA (Y.C.K., M.C.-M., V.V.).
  • Huber TB; Scripps Research, Center for Metabolomics, San Diego, CA (A.P., G.S., M.M.R.).
  • Laugesen E; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles (A.P.).
  • Zeller T; Departments of Biomedicine (A.M.B., F.D., E.K., J.J., R.A.F., M.C., M.M.R.), Aarhus University, Denmark.
  • Chrysopoulou M; III Department of Medicine and Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.H., M.L., E.H., T.B.H., M.M.R.).
  • Saez-Rodriguez J; Department of Cardiology, University Heart and Vascular Center Hamburg, Germany (B.S., S.B., P.K., T.Z., C.M.).
  • Magnussen C; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany (B.S., J.R., S.B., P.K., T.Z., C.M., T.E., F.C.).
  • Eschenhagen T; Department of Cardiology, University Heart and Vascular Center Hamburg, Germany (B.S., S.B., P.K., T.Z., C.M.).
  • Staruschenko A; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany (B.S., J.R., S.B., P.K., T.Z., C.M., T.E., F.C.).
  • Siuzdak G; Institute of Cardiovascular Sciences, University of Birmingham, United Kingdom (P.K.).
  • Poulsen PL; III Department of Medicine and Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.H., M.L., E.H., T.B.H., M.M.R.).
  • Schwab C; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark (S.G., E.L.).
  • Cuello F; Diagnostic Centre, Silkeborg Regional Hospital, Denmark (E.L.).
  • Vallon V; Department of Cardiology, University Heart and Vascular Center Hamburg, Germany (B.S., S.B., P.K., T.Z., C.M.).
  • Rinschen MM; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany (B.S., J.R., S.B., P.K., T.Z., C.M., T.E., F.C.).
Circulation ; 149(11): 860-884, 2024 03 12.
Article en En | MEDLINE | ID: mdl-38152989
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ésteres del Ácido Sulfúrico / Cresoles / Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 / Células Madre Pluripotentes Inducidas / Inhibidores del Cotransportador de Sodio-Glucosa 2 Límite: Animals / Humans Idioma: En Revista: Circulation Año: 2024 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ésteres del Ácido Sulfúrico / Cresoles / Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 / Células Madre Pluripotentes Inducidas / Inhibidores del Cotransportador de Sodio-Glucosa 2 Límite: Animals / Humans Idioma: En Revista: Circulation Año: 2024 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos