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mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy

Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-rel...

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Autores principales: Saha, Sumit, Fang, Xianjun, Green, Christopher D., Das, Anindita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606418/
https://www.ncbi.nlm.nih.gov/pubmed/37894760
http://dx.doi.org/10.3390/ijms242015078
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author Saha, Sumit
Fang, Xianjun
Green, Christopher D.
Das, Anindita
author_facet Saha, Sumit
Fang, Xianjun
Green, Christopher D.
Das, Anindita
author_sort Saha, Sumit
collection PubMed
description Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium–glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.
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spelling pubmed-106064182023-10-28 mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy Saha, Sumit Fang, Xianjun Green, Christopher D. Das, Anindita Int J Mol Sci Review Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium–glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling. MDPI 2023-10-11 /pmc/articles/PMC10606418/ /pubmed/37894760 http://dx.doi.org/10.3390/ijms242015078 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Saha, Sumit
Fang, Xianjun
Green, Christopher D.
Das, Anindita
mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
title mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
title_full mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
title_fullStr mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
title_full_unstemmed mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
title_short mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
title_sort mtorc1 and sglt2 inhibitors—a therapeutic perspective for diabetic cardiomyopathy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606418/
https://www.ncbi.nlm.nih.gov/pubmed/37894760
http://dx.doi.org/10.3390/ijms242015078
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