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SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism

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Abstract

Heart failure (HF) often coexists with insulin resistance (IR), and the incidence of HF in type 2 diabetes mellitus (T2DM) patients is significantly higher. The reciprocal relationship between HF and IR has long been recognized, and the integration complicates the therapy of both. A number of mechanisms ascribe to the progression of cardiac IR, in which the main factors are the shift of myocardial substrate metabolism. Studies have found that SGLT2 inhibitors, an anti-diabetic drug, can improve the cardiac prognosis of patients with T2DM, which may be at least partially due to the relief of cardiac IR. Basic and clinical studies have revealed the important role of cardiac IR in the pathogenesis and progression of HF, and studies suggest that energy metabolism plays an important role in the pathogenesis of cardiac IR and HF. SGLT2 inhibitors mediated cardiovascular benefits through various mechanisms such as improving substrate utilization and improving myocardial energy. The regulation of SGLT2 inhibitors on cardiac energy status including carbohydrates, fatty acids (FA), amino acids and ketones, ATP transfer to the cytoplasm, and mitochondrial functional status have received extensive attention in HF, but its specific mechanism of action is still unclear. Therefore, this article reviews the relationship between IR and HF from the perspective of energy metabolism; subsequently, targeting energy metabolism discusses the pivotal role of SGLT2 inhibitors in improving cardiac IR and HF based on basic and clinical research evidences, and sought to clarify the molecular mechanism involved. (Fig. 1).

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Abbreviations

ACC:

Acetyl CoA carboxylase

ADA:

The American Diabetes Association

AMPK:

AMP-activated protein kinase

BCATm:

Branched chain aminotransferase in mitochondrial

BCKDH:

Branched chain ketoacid dehydrogenase

BMPR2:

Bone morphogenetic protein receptor type 2

BDH1:

β-Hydroxybutyrate dehydrogenase 1

βOHB:

β-Hydroxybutyrate

CPT1/2:

Carnitine palmitoyltransferase 1/2

DPP-4 inhibitors:

Dipeptidyl peptidase-4 inhibitors

EASD:

The European Association for the Study of Diabetes

ESC:

The European Society of Cardiology

FA:

Fatty acid

G-6-P:

Glucose-6-phosphate

GLP-1:

Glucagon-like peptide-1

MACE:

Major adverse cardiovascular events

MCD:

Malonyl-CoA decarboxylase

mTOR:

Mechanistic target of rapamycin

MCT:

Monocarborxylat transporter

MPC:

Mitochondrial pyruvate carrier

NT-proBNP:

Amino-terminal pro-B-type natriuretic peptide

PDH:

Pyruvate dehydrogenase

SBP:

Systolic blood pressure

SCOT:

Succinyl-CoA transferase

SNS:

Sympathetic nervous system

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Acknowledgements

We kindly thank Mr. Guanwei Fan. for editing the manuscript.

Funding

This review was supported by grants from the National Key Subject of Drug Innovation (2019ZX09201005-007), the National Key R&D Program of China (2018YFC1704500), the National Natural Science Foundation of China (81,774,050), and Tianjin Science Foundation for Distinguished Young Scholars (17JCJQJC46200).

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  1. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China

    Xiaodan Wang, Jingyu Ni, Rui Guo, Lan Li, Jing Su & Guanwei Fan

  2. Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization, Huanggang Normal University, Huanggang, 438000, China

    Feng He

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Xiaodan Wang, Guanwei Fan, and Jingyu Ni—concept and original draft; Xiaodan Wang, Jingyu Ni, Rui Guo, and Lan Li—literature search and data extraction; Xiaodan Wang, Guanwei Fan, Jing Su, and Feng He—assessed quality of evidence; Xiaodan Wang, Jing Su, Feng He, and Guanwei Fan—spell check and grammar check; Xiaodan Wang, Guanwei Fan, Jingyu Ni, Rui Guo, Lan Li, Jing Su, and Feng He—writing and final approval of the manuscript.

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Wang, X., Ni, J., Guo, R. et al. SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism. Heart Fail Rev 27, 961–980 (2022). https://doi.org/10.1007/s10741-021-10096-8

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