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Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2018 Feb 01; Vol. 114 (2), pp. 336-346. - Publication Year :
- 2018
-
Abstract
- Aims: In patients with cardiovascular disease, epicardial adipose tissue (EAT) is characterized by insulin resistance, high pro-inflammatory chemokines, and low differentiation ability. As dapagliflozin reduces body fat and cardiovascular events in diabetic patients, we would like to know its effect on EAT and subcutaneous adipose tissue (SAT).<br />Methods and Results: Adipose samples were obtained from 52 patients undergoing heart surgery. Sodium-glucose cotransporter 2 (SGLT2) expression was determined by real-time polymerase chain reaction (n = 20), western blot, and immunohistochemistry. Fat explants (n = 21) were treated with dapagliflozin and/or insulin and glucose transporters expression measured. Glucose, free fatty acid, and adipokine levels (by array) were measured in the EAT secretomes, which were then tested on human coronary endothelial cells using wound healing assays. Glucose uptake was also measured using the fluorescent glucose analogue (6NBDG) in differentiated stromal vascular cells (SVCs) from the fat pads (n = 11). Finally, dapagliflozin-induced adipocyte differentiation was assessed from the levels of fat droplets (AdipoRed staining) and of perilipin. SGLT2 was expressed in EAT. Dapagliflozin increased glucose uptake (20.95 ± 4.4 mg/dL vs. 12.97 ± 4.1 mg/dL; P < 0.001) and glucose transporter type 4 (2.09 ± 0.3 fold change; P < 0.01) in EAT. Moreover, dapagliflozin reduced the secretion levels of chemokines and benefited wound healing in endothelial cells (0.21 ± 0.05 vs. 0.38 ± 0.08 open wound; P < 0.05). Finally, chronic treatment with dapagliflozin improved the differentiation of SVC, confirmed by AdipoRed staining [539 ± 142 arbitrary units (a.u.) vs. 473 ± 136 a.u.; P < 0.01] and perilipin expression levels (121 ± 10 vs. 84 ± 11 a.u.).<br />Conclusions: Dapagliflozin increased glucose uptake, reduced the secretion of pro-inflammatory chemokines (with a beneficial effect on the healing of human coronary artery endothelial cells), and improved the differentiation of EAT cells. These results suggest a new protective pathway for this drug on EAT from patients with cardiovascular disease.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.)
- Subjects :
- Adipokines metabolism
Adipose Tissue, White immunology
Adipose Tissue, White metabolism
Endothelial Cells drug effects
Endothelial Cells immunology
Endothelial Cells metabolism
Glucose metabolism
Humans
Insulin pharmacology
Paracrine Communication drug effects
Pericardium
Sodium-Glucose Transporter 1 metabolism
Sodium-Glucose Transporter 2 metabolism
Subcutaneous Fat immunology
Subcutaneous Fat metabolism
Adipogenesis drug effects
Adipose Tissue, White drug effects
Benzhydryl Compounds pharmacology
Chemokines metabolism
Glucosides pharmacology
Inflammation Mediators metabolism
Insulin Resistance
Sodium-Glucose Transporter 2 Inhibitors pharmacology
Subcutaneous Fat drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 114
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 29016744
- Full Text :
- https://doi.org/10.1093/cvr/cvx186