Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy

Xi, Yangbo; Chen, Dongping; Dong, Zhihui; Zhang, Jinhua; Lam, Hingcheung; He, Jiading; Du, Keyi; Chen, Can; Guo, Jun; Xiao, Jing

doi:10.3389/fcvm.2022.999254

Cited by 13 publications

(18 citation statements)

References 44 publications

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“…4 studies ( 12 , 24 , 27 , 45 ) reported weight loss. 7 studies ( 11 , 15 , 19 , 20 , 30 , 32 , 41 ) showed no differences in changes to body weight and 1 study ( 13 ) reported increases in body weight. Table 3 displayed the specific results.…”

Section: Resultsmentioning

confidence: 98%

“…The FA metabolism-related indicators in heart samples were as follows: the content of FA translocase (CD36), carnitine palmitoyl transferase-1 (CPT-1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α), peroxisome proliferator-activated receptor α (PPARα), the ratio of phosphorylated-adenosine monophosphate-activated protein kinase to adenosine monophosphate-activated protein kinase (p-AMPK/AMPK), the ratio of phosphorylated-acetyl CoA carboxylase to acetyl CoA carboxylase (p-ACC/ACC), myocardial TG content, myocardial FA uptake, epicardial fat volume, the total number of lipid droplets in cardiomyocytes, and proteomics and metabolomics of myocardial tissue (details were shown in Table 3 ). Among these, 6 studies showed that SGLT2i increased the FA metabolism of the heart ( 12 , 15 , 30 , 41 , 42 , 44 ), including the expressions of FA uptake-related transporter protein CD36, FA from cytoplasm into mitochondria related protein CPT-1, FA oxidation-related proteins (PGC1-α, PPARα, AMPK, and ACC); notably, the EF values of 5/6 studies ( 12 , 30 , 41 , 42 , 44 ) were >50% which were similar to the EF values of HFpEF. Cardiac FA metabolism was reduced in 1 study ( 13 ) and remained unchanged in 2 studies ( 11 , 32 ).…”

Section: Resultsmentioning

confidence: 99%

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The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

Su,

Ji,

et al. 2023

Front. Cardiovasc. Med.

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Background/aimsTo investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism.MethodsA systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality.ResultsThe results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i.ConclusionSGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases.Systematic review registrationhttps://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

Su,

Ji,

et al. 2023

Front. Cardiovasc. Med.

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“…Multi-omics analysis showed that EMPA could regulate and partially restore the levels of multiple metabolites related to stress in cardiomyocytes under high glucose environment, alleviating lipid toxicity 34 . Enhanced diabetic cardiac fatty acid (FA) metabolism and perturbations in the biosynthesis of unsaturated fatty acid and arachidonic acid metabolism are potential drivers of the cardiovascular benefits of EMPA 35 . Animal experiments have also demonstrated that fatty acid oxidation is one of the targets of EMPA therapy in db/db mouse hearts 36 .…”

Section: Discussionmentioning

confidence: 99%

Exploring shared therapeutic targets in diabetic cardiomyopathy and diabetic foot ulcers through bioinformatics analysis

Wu,

Yang,

Wang

et al. 2024

Sci Rep

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Advanced diabetic cardiomyopathy (DCM) patients are often accompanied by severe peripheral artery disease. For patients with DCM combined with diabetic foot ulcer (DFU), there are currently no good therapeutic targets and drugs. Here, we investigated the underlying network of molecular actions associated with the occurrence of these two complications. The datasets were downloaded from the Gene Expression Omnibus (GEO) database. We performed enrichment and protein–protein interaction analyses, and screened for hub genes. Construct transcription factors (TFs) and microRNAs regulatory networks for validated hub genes. Finally, drug prediction and molecular docking verification were performed. We identified 299 common differentially expressed genes (DEGs), many of which were involved in inflammation and lipid metabolism. 6 DEGs were identified as hub genes (PPARG, JUN, SLC2A1, CD4, SCARB1 and SERPINE1). These 6 hub genes were associated with inflammation and immune response. We identified 31 common TFs and 2 key miRNAs closely related to hub genes. Interestingly, our study suggested that fenofibrate, a lipid-lowering medication, holds promise as a potential treatment for DCM combined with DFU due to its stable binding to the identified hub genes. Here, we revealed a network involves a common target for DCM and DFU. Understanding these networks and hub genes is pivotal for advancing our comprehension of the multifaceted complications of diabetes and facilitating the development of future therapeutic interventions.

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“…There have been several studies showing alterations in circulating metabolites including amino acids caused by treatment with an SGLT2i [32][33][34][35], but there have been no study focusing on BAIBA, a non-proteinogenic amino acid also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid. In the present study, the proportion of patients in whom plasma BAIBA was detected was higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i.…”

Section: Discussionmentioning

confidence: 99%

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Katano

Yano

Kouzu

et al. 2022

Cardiovasc Diabetol

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Aims The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). Methods We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. Results Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. Conclusion SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

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Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy

Cited by 13 publications

References 44 publications

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

Exploring shared therapeutic targets in diabetic cardiomyopathy and diabetic foot ulcers through bioinformatics analysis

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

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