Sanz RL, García Menéndez S, Inserra F, Ferder L, Manucha W. Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence. World J Exp Med 2024; 14(2): 91519 [DOI: 10.5493/wjem.v14.i2.91519]
Corresponding Author of This Article
Walter Manucha, PhD, Adjunct Professor, Department of Pathology, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Campus Universitario Uncuyo, Mendoza 5500, Argentina. wmanucha@fcm.uncu.edu.ar
Research Domain of This Article
Pharmacology & Pharmacy
Article-Type of This Article
Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Exp Med. Jun 20, 2024; 14(2): 91519 Published online Jun 20, 2024. doi: 10.5493/wjem.v14.i2.91519
Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence
Raúl Lelio Sanz, Sebastián García Menéndez, Felipe Inserra, Leon Ferder, Walter Manucha
Raúl Lelio Sanz, Sebastián García Menéndez, Walter Manucha, Department of Pathology, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza 5500, Argentina
Sebastián García Menéndez, Walter Manucha, Department of Pharmacology, Instituto de Medicina y Biología Experimental de Cuyo, Centro Científico Tecnológico, Mendoza 5500, Argentina
Felipe Inserra, Department of Nephrology, Universidad de Maimónides, Ciudad Autónoma de Buenos Aires C1405, Argentina
Leon Ferder, Department of Cardiology, Universidad de Maimónides, Ciudad Autónoma de Buenos Aires C1405, Argentina
Author contributions: Sanz RL, García Menéndez S, Inserra F, Ferder L, Manucha W did substantial contributions to conception and design of the manuscript, made critical revisions related to the important intellectual content of the manuscript, and provided final approval of the version of the article to be published.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Walter Manucha, PhD, Adjunct Professor, Department of Pathology, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Campus Universitario Uncuyo, Mendoza 5500, Argentina. wmanucha@fcm.uncu.edu.ar
Received: December 29, 2023 Revised: February 7, 2024 Accepted: April 11, 2024 Published online: June 20, 2024 Processing time: 172 Days and 14.1 Hours
Abstract
Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5’ adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.
Core Tip: Sodium-glucose cotransporter-2 inhibitors, diabetes drugs, unlock tissue protection via diverse pathways. They boost mitochondrial efficiency, curb oxidative stress and inflammation, and enhance autophagy. Clinical trials show cardiovascular benefits, suggesting immense potential beyond diabetes and even towards anti-aging therapy.
