Mechanisms of sodium-glucose cotransporter-2 inhibition: insights from large-scale proteomics

Ferrannini, E., Murthy, A. C., Lee, Y.-h., Muscelli, E., Weiss, S., Ostroff, R. M., Sattar, N. , Williams, S. A. and Ganz, P. (2020) Mechanisms of sodium-glucose cotransporter-2 inhibition: insights from large-scale proteomics. Diabetes Care, 43(9), pp. 2183-2189. (doi: 10.2337/dc20-0456) (PMID:32527800)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Sattar, Professor Naveed
Authors: Ferrannini, E., Murthy, A. C., Lee, Y.-h., Muscelli, E., Weiss, S., Ostroff, R. M., Sattar, N., Williams, S. A., and Ganz, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Diabetes Care
Publisher:American Diabetes Association
ISSN (Online):1935-5548
Published Online:11 June 2020
Copyright Holders:Copyright © 2020 by the American Diabetes Association
First Published:First published in Diabetes Care 43(9): 2183-2189
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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