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D'Onofrio N, Sardu C, Trotta MC, et al. Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment. Mol Metab. 2021;54:101337doi: 10.1016/j.molmet.2021.101337.
D'Onofrio, N., Sardu, C., Trotta, M. C., Scisciola, L., Turriziani, F., Ferraraccio, F., Panarese, I., Petrella, L., Fanelli, M., Modugno, P., Massetti, M., Marfella, L. V., Sasso, F. C., Rizzo, M. R., Barbieri, M., Furbatto, F., Minicucci, F., Mauro, C., Federici, M., Balestrieri, M. L., Paolisso, G., & Marfella, R. (2021). Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment. Molecular metabolism, 54101337. https://doi.org/10.1016/j.molmet.2021.101337
D'Onofrio, Nunzia, et al. "Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment." Molecular metabolism vol. 54 (2021): 101337. doi: https://doi.org/10.1016/j.molmet.2021.101337
D'Onofrio N, Sardu C, Trotta MC, Scisciola L, Turriziani F, Ferraraccio F, Panarese I, Petrella L, Fanelli M, Modugno P, Massetti M, Marfella LV, Sasso FC, Rizzo MR, Barbieri M, Furbatto F, Minicucci F, Mauro C, Federici M, Balestrieri ML, Paolisso G, Marfella R. Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment. Mol Metab. 2021 Sep 07;54:101337. doi: 10.1016/j.molmet.2021.101337. Epub 2021 Sep 07. PMID: 34500107; PMCID: PMC8473552.
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Mol Metab. 2021 Sep 07;54:101337. doi: 10.1016/j.molmet.2021.101337. Epub 2021 Sep 07.

Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment.

Molecular metabolism

Nunzia D'Onofrio, Celestino Sardu, Maria Consiglia Trotta, Lucia Scisciola, Fabrizio Turriziani, Franca Ferraraccio, Iacopo Panarese, Lella Petrella, Mara Fanelli, Piero Modugno, Massimo Massetti, Ludovica Vittoria Marfella, Ferdinando Carlo Sasso, Maria Rosaria Rizzo, Michelangela Barbieri, Fulvio Furbatto, Fabio Minicucci, Ciro Mauro, Massimo Federici, Maria Luisa Balestrieri, Giuseppe Paolisso, Raffaele Marfella

Affiliations

  1. Department of Precision Medicine, the University of Campania "Luigi Vanvitelli,", Italy.
  2. Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli,", Italy.
  3. Department of Experimental Medicine, Section of Pharmacology, University of Campania "Luigi Vanvitelli,", Italy.
  4. Department of Mental Health and Public Medicine, Section of Statistic, the University of Campania "Luigi Vanvitelli,", Naples, Italy.
  5. Laboratory of Molecular Oncology, Gemelli Molise SpA, Campobasso, Italy.
  6. Department of Cardiovascular Medicine, Gemelli Molise SpA, Campobasso, Italy.
  7. Department of Cardiology, Hospital Cardarelli, Naples, Italy.
  8. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  9. Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli,", Italy; Mediterranea Cardiocentro, Naples, Italy.
  10. Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli,", Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address: [email protected].

PMID: 34500107 PMCID: PMC8473552 DOI: 10.1016/j.molmet.2021.101337

Abstract

OBJECTIVE: We evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients.

METHODS: Plaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up.

RESULTS: Compared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P < 0.01). Among patient with diabetes, the current SGLT2i users presented a significantly lower rate of MACE through 2 years compared to non-SGLT2i users (P < 0.05).

CONCLUSIONS: These findings unveil a critical involvement of the SGLT2/SIRT6 pathway in the inflammatory process of diabetic atherosclerotic lesions and suggest its possible favorable modulation by SGLT2i.

Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.

Keywords: Atherosclerosis; Inflammation; SGLT2; Sirtuin-6; Type 2 diabetes mellitus

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