Mechanisms of Sodium-Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics.
| Autor: | Ferrannini E; CNR Institute of Clinical Physiology, Pisa, Italy ferranni@ifc.cnr.it., Murthy AC; Cardiovascular Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA., Lee YH; Department of Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea., Muscelli E; CNR Institute of Clinical Physiology, Pisa, Italy., Weiss S; SomaLogic, Inc., Boulder, CO., Ostroff RM; SomaLogic, Inc., Boulder, CO., Sattar N; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K., Williams SA; SomaLogic, Inc., Boulder, CO., Ganz P; Zuckerberg San Francisco General Hospital, University of California, San Francisco, CA. |
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| Jazyk: | angličtina |
| Zdroj: | Diabetes care [Diabetes Care] 2020 Sep; Vol. 43 (9), pp. 2183-2189. Date of Electronic Publication: 2020 Jun 11. |
| DOI: | 10.2337/dc20-0456 |
| Abstrakt: | Objective: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. Research Design and Methods: Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. Results: Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid-binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. Conclusions: SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design. (© 2020 by the American Diabetes Association.) |
| Databáze: | MEDLINE |
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