P1592Novel protective mechanisms of dapagliflozin on epicardial adipose tissue with insulin resistance, inflammatory chemokines production and low differentiation ability

AbstractAimsIn patients with cardiovascular disease, epicardial adipose tissue (EAT) is characterized by insulin resistance, high pro-inflammatory chemokines, and low differentiation ability. As dapagliflozin reduces body fat and cardiovascular events in diabetic patients, we would like to know its effect on EAT and subcutaneous adipose tissue (SAT).Methods and resultsAdipose samples were obtained from 52 patients undergoing heart surgery. Sodium-glucose cotransporter 2 (SGLT2) expression was determined by real-time polymerase chain reaction (n = 20), western blot, and immunohistochemistry. Fat explants (n = 21) were treated with dapagliflozin and/or insulin and glucose transporters expression measured. Glucose, free fatty acid, and adipokine levels (by array) were measured in the EAT secretomes, which were then tested on human coronary endothelial cells using wound healing assays. Glucose uptake was also measured using the fluorescent glucose analogue (6NBDG) in differentiated stromal vascular cells (SVCs) from the fat pads (n = 11). Finally, dapagliflozin-induced adipocyte differentiation was assessed from the levels of fat droplets (AdipoRed staining) and of perilipin. SGLT2 was expressed in EAT. Dapagliflozin increased glucose uptake (20.95 ± 4.4 mg/dL vs. 12.97 ± 4.1 mg/dL; P < 0.001) and glucose transporter type 4 (2.09 ± 0.3 fold change; P < 0.01) in EAT. Moreover, dapagliflozin reduced the secretion levels of chemokines and benefited wound healing in endothelial cells (0.21 ± 0.05 vs. 0.38 ± 0.08 open wound; P < 0.05). Finally, chronic treatment with dapagliflozin improved the differentiation of SVC, confirmed by AdipoRed staining [539 ± 142 arbitrary units (a.u.) vs. 473 ± 136 a.u.; P < 0.01] and perilipin expression levels (121 ± 10 vs. 84 ± 11 a.u.).ConclusionsDapagliflozin increased glucose uptake, reduced the secretion of pro-inflammatory chemokines (with a beneficial effect on the healing of human coronary artery endothelial cells), and improved the differentiation of EAT cells. These results suggest a new protective pathway for this drug on EAT from patients with cardiovascular disease.

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The Relationship between Epicardial Adipose Tissue Thickness and Serum Interleukin-17a Level in Patients with Isolated Metabolic Syndrome

Biomolecules ◽

10.3390/biom9030097 ◽

2019 ◽

Vol 9 (3) ◽

pp. 97 ◽

Cited By ~ 4

Author(s):

Esra Demir ◽

Nazmiye Harmankaya ◽

İrem Kıraç Utku ◽

Gönül Açıksarı ◽

Turgut Uygun ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Epicardial Adipose Tissue ◽

Control Group ◽

Model Assessment ◽

Tissue Thickness ◽

The Metabolic Syndrome ◽

Epicardial Adipose Tissue Thickness ◽

The Relationship

In this study, it was aimed to investigate the relationship between the epicardial adipose tissue thickness (EATT) and serum IL-17A level insulin resistance in metabolic syndrome patients. This study enrolled a total of 160 subjects, of whom 80 were consecutive patients who applied to our outpatient clinic and were diagnosed with metabolic syndrome, and the other 80 were consecutive patients who were part of the control group with similar age and demographics in whom the metabolic syndrome was excluded. The metabolic syndrome diagnosis was made according to International Diabetes Federation (IDF)-2005 criteria. EATT was measured with transthoracic echocardiography (TTE) in the subjects. IL-17A serum levels were determined using the ELISA method. Fasting blood glucose, HDL, triglyceride, and fasting insulin levels were significantly higher in the metabolic syndrome group compared to the control group. In addition, the metabolic syndrome group had significantly higher high-sensitivity C-reactive protein (hs-CRP) and Homeostatic Model Assessment Insulin Resistance (HOMA-IR) levels than the control group. Similarly, serum IL-17A levels were significantly elevated in the metabolic syndrome group compared to the control group statistically (p < 0.001). As well, EATT was higher in the metabolic syndrome than the control group. Conclusion: By virtue of their proinflammatory properties, EATT and IL-17 may play an important role in the pathogenesis of the metabolic syndrome.

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Increased Subcutaneous and Epicardial Adipose Tissue Production of Proinflammatory Cytokines in Cardiac Surgery Patients: Possible Role in Postoperative Insulin Resistance

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-1044 ◽

2006 ◽

Vol 91 (11) ◽

pp. 4620-4627 ◽

Cited By ~ 158

Author(s):

Jaromir Kremen ◽

Marketa Dolinkova ◽

Jana Krajickova ◽

Jan Blaha ◽

Katerina Anderlova ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Cardiac Surgery ◽

Mrna Expression ◽

Proinflammatory Cytokines ◽

Epicardial Adipose Tissue ◽

Monocyte Chemoattractant Protein 1 ◽

Elective Cardiac Surgery ◽

Tnf Α ◽

History Of

Abstract Context: Hyperglycemia and insulin resistance frequently occur in critically ill patients even without a history of diabetes. Objective: Our objective was to study the role of adipose tissue hormonal production in the development of insulin resistance in cardiac surgery patients. Participants, Interventions, and Settings: Fifteen patients with elective cardiac surgery underwent blood sampling before, at the end, and 6, 12, 24, 48, and 120 h after the end of their operation. Epicardial and sc adipose tissue sampling was done at the beginning and at the end of surgery in the Department of Cardiac Surgery. Main Outcome Measures: We measured serum concentrations and sc and epicardial adipose tissue mRNA expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), TNF-α, leptin, resistin, and adiponectin and sc and epicardial adipose tissue mRNA expression of CD14, CD45, and CD68. Results: The rate of insulin infusion required to maintain euglycemia increased up to 7-fold 12 h after the operation, suggesting the development of insulin resistance. Serum IL-6 levels increased 43-fold 12 h after surgery. MCP-1 peaked 6-fold at the end of surgery. Smaller peaks of TNF-α and leptin appeared 6 and 12 h after surgery, respectively. Resistin levels peaked 4-fold 24 h after surgery, but adiponectin levels were not significantly affected. TNF-α and CD45 mRNA expression increased markedly during the operation in sc adipose tissue. IL-6, resistin, and MCP-1 mRNA expression increased in both sc and epicardial adipose tissue. Leptin, adiponectin, CD14, and CD68 mRNA expression did not change significantly. Conclusions: Both sc and epicardial adipose tissue is a source of proinflammatory cytokines in cardiac surgery patients and may contribute to the development of postoperative insulin resistance.

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Increased angiotensinogen production in epicardial adipose tissue during cardiac surgery: Possible role in a postoperative insulin resistance

Physiological Research ◽

10.33549/physiolres.931315 ◽

2008 ◽

pp. 911-917

Author(s):

T Roubíček ◽

M Dolinková ◽

J Bláha ◽

D Haluzíková ◽

L Bošanská ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Cardiac Surgery ◽

Blood Glucose ◽

Angiotensin Ii ◽

Epicardial Adipose Tissue ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin System

Critical illness induces among other events production of proinflammatory cytokines that in turn interfere with insulin signaling cascade and induce insulin resistance on a postreceptor level. Recently, local renin-angiotensin system of adipose tissue has been suggested as a possible contributor to the development of insulin resistance in patients with obesity. The aim of our study was to determine local changes of the renin-angiotensin system of subcutaneous and epicardial adipose tissue during a major cardiac surgery, which may serve as a model of an acute stress potentially affecting endocrine function of adipose tissue. Ten patients undergoing elective cardiac surgery were included into the study. Blood samples and samples of subcutaneous and epicardial adipose tissue were collected at the beginning and at the end of the surgery. Blood glucose, serum insulin and adiponectin levels were measured and mRNA for angiotensinogen, angiotensin-converting enzyme and angiotensin II type 1 receptor were determined in adipose tissue samples using RT PCR. Cardiac surgery significantly increased both insulin and blood glucose levels suggesting the development of insulin resistance, while serum adiponectin levels did not change. Expression of angiotensinogen mRNA significantly increased in epicardial adipose tissue at the end of surgery relative to baseline but remained unchanged in subcutaneous adipose tissue. Fat expression of angiotensin-converting enzyme and type 1 receptor for angiotensin II were not affected by surgery. Our study suggests that increased angiotensinogen production in epicardial adipose tissue may contribute to the development of postoperative insulin resistance.

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Epicardial Adipose Tissue and Insulin Resistance in Obese Subjects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-1087 ◽

2005 ◽

Vol 90 (11) ◽

pp. 6300-6302 ◽

Cited By ~ 216

Author(s):

Gianluca Iacobellis ◽

Frida Leonetti

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Epicardial Adipose Tissue ◽

Obese Subjects

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Association of Region‐Specific Cardiac Adiposity With Dysglycemia and New‐Onset Diabetes

Journal of the American Heart Association ◽

10.1161/jaha.121.021921 ◽

2021 ◽

Author(s):

Kuo‐Tzu Sung ◽

Jen‐Yuan Kuo ◽

Chun‐Ho Yun ◽

Yueh‐Hung Lin ◽

Jui‐Peng Tsai ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Epicardial Adipose Tissue ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

Onset Diabetes ◽

Visceral Adipose ◽

Periaortic Fat ◽

New Onset

Background Visceral adipose tissue is assumed to be an important indicator for insulin resistance and diabetes beyond overweight/obesity. We hypothesized that region‐specific visceral adipose tissue may regulate differential biological effects for new‐onset diabetes regardless of overall obesity. Methods and Results We quantified various visceral adipose tissue measures, including epicardial adipose tissue, paracardial adipose tissue, interatrial fat, periaortic fat, and thoracic aortic adipose tissue in 1039 consecutive asymptomatic participants who underwent multidetector computed tomography. We explored the associations of visceral adipose tissue with baseline dysglycemic indices and new‐onset diabetes. Epicardial adipose tissue, paracardial adipose tissue, interatrial fat, periaortic fat, and thoracic aortic adipose tissue were differentially and independently associated with dysglycemic indices (fasting glucose, postprandial glucose, HbA1c, and homeostasis model assessment of insulin resistance) beyond anthropometric measures. The superimposition of interatrial fat and thoracic aortic adipose tissue on age, sex, body mass index, and baseline homeostasis model assessment of insulin resistance expanded the likelihood of baseline diabetes (from 67.2 to 86.0 and 64.4 to 70.8, P for ∆ ꭕ 2 : <0.001 and 0.011, respectively). Compared with the first tertile, the highest interatrial fat tertile showed a nearly doubled risk for new‐onset diabetes (hazard ratio, 2.09 [95% CI, 1.38–3.15], P <0.001) after adjusting for Chinese Visceral Adiposity Index. Conclusions Region‐specific visceral adiposity may not perform equally in discriminating baseline dysglycemia or diabetes, and showed differential predictive performance in new‐onset diabetes. Our data suggested that interatrial fat may serve as a potential marker for new‐onset diabetes.

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Eicosapentaenoic Acid Regulates Inflammatory Pathways through Modulation of Transcripts and miRNA in Adipose Tissue of Obese Mice

Biomolecules ◽

10.3390/biom10091292 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1292

Author(s):

Theresa Ramalho ◽

Mandana Pahlavani ◽

Nishan Kalupahana ◽

Nadeeja Wijayatunga ◽

Latha Ramalingam ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Eicosapentaenoic Acid ◽

Positive Association ◽

Lipid Mediator ◽

Obese Mice ◽

Protective Mechanisms ◽

Rna Profiling ◽

Inflammatory Pathways ◽

Regulatory Effects

This study aims to investigate the global profiling of genes and miRNAs expression to explore the regulatory effects of eicosapentaenoic acid (EPA) in visceral adipose tissue (VAT) of obese mice. We used male mice, fed either a high-fat diet (HF) or HF supplemented with EPA (HF-EPA), for 11 weeks. RNA, and small RNA profiling, were performed by RNAseq analysis. We conducted analyses using Ingenuity Pathway Analysis software (IPA®) and validated candidate genes and miRNAs related to lipid mediators and inflammatory pathways using qRT-PCR. We identified 153 genes differentially downregulated, and 62 microRNAs differentially expressed in VAT from HF-EPA compared to HF. Genes with a positive association with inflammation, chemotaxis, insulin resistance, and inflammatory cell death, such as Irf5, Alox5ap, Tlrs, Cd84, Ccr5, Ccl9, and Casp1, were downregulated by EPA. Moreover, EPA significantly reduced LTB4 levels, a lipid mediator with a central role in inflammation and insulin resistance in obesity. The pathways and mRNA/microRNA interactions identified in our study corroborated with data validated for inflammatory genes and miRNAs. Together, our results identified key VAT inflammatory targets and pathways, which are regulated by EPA. These targets merit further investigation to better understand the protective mechanisms of EPA in obesity-associated inflammation.

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Effects of metformin on epicardial adipose tissue and atrial electromechanical delay of obese children with insulin resistance

Cardiology in the Young ◽

10.1017/s1047951120002103 ◽

2020 ◽

Vol 30 (10) ◽

pp. 1429-1432

Author(s):

Hatice Güneş ◽

Hakan Güneş ◽

Şebnem Özmen ◽

Enes Çelik ◽

Fatih Temiz

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Epicardial Adipose Tissue ◽

Glucose Metabolism Disorders ◽

Obese Children ◽

Tissue Thickness ◽

Electromechanical Delay ◽

Atrial Electromechanical Delay ◽

Epicardial Adipose Tissue Thickness ◽

Metformin Monotherapy

AbstractIntroduction:Obesity is usually related to insulin resistance and glucose metabolism disorders. The relationship between insulin resistance and epicardial adipose tissue and atrial electromechanical delay has been described in previous studies.Aim:This study aims to demonstrate the effects of metformin on epicardial adipose tissue and electromechanical delay in patients using metformin for insulin resistance.Materials and methods:A total of 30 patients using metformin for insulin resistance were included in the study. Pre-treatment and post-treatment epicardial adipose tissue and electromechanical delay were evaluated.Results:There was a statistically significant decrease in epicardial adipose tissue thickness after 3 months of metformin therapy (6.4 ± 2.1 versus 4.7 ± 2.0; p = 0.008). Furthermore, the inter-atrial and intra-atrial electromechanical delay also significantly decreased after 3 months of metformin monotherapy (23.6 ± 8.2 versus 18.1 ± 5.8; p < 0.001, 9.1 ± 2.9 versus 6.3 ± 3.6; p = 0.003, respectively).Conclusion:In this study, we show that metformin monotherapy significantly decreases epicardial adipose tissue thickness and electromechanical delay in obese children.

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Hypertrophy and Insulin Resistance of Epicardial Adipose Tissue Adipocytes: Association with the Coronary Artery Disease Severity

Biomedicines ◽

10.3390/biomedicines9010064 ◽

2021 ◽

Vol 9 (1) ◽

pp. 64

Author(s):

Natalia V. Naryzhnaya ◽

Olga A. Koshelskaya ◽

Irina V. Kologrivova ◽

Olga A. Kharitonova ◽

Vladimir V. Evtushenko ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Coronary Artery ◽

Epicardial Adipose Tissue ◽

Bypass Graft ◽

Gensini Score ◽

Adipocyte Hypertrophy ◽

Average Size ◽

Nonparametric Correlation ◽

Intracellular Redox

Changes in the structural and functional characteristics of the epicardial adipose tissue (EAT) are recognized as one of the factors in the development of cardiometabolic diseases. However, the generally accepted quantitative assessment of the accumulation of EAT does not reflect the size of adipocyte and presence of adipocyte hypertrophy in this fat depot. Overall contribution of adipocyte hypertrophy to the development and progression of coronary atherosclerosis remains unexplored. Objective: To compare the morphological characteristics of EAT adipocyte and its sensitivity to insulin with the CAD severity, as well as to identify potential factors involved in the realization of this relationship. The present study involved 24 patients (m/f 16/8) aged 53–72 years with stable CAD, who underwent coronary artery bypass graft surgery. Adipocytes were isolated enzymatically from EAT explants obtained during the operation. The severity of CAD was assessed by calculating the Gensini score according to selective coronary angiography. Insulin resistance of EAT adipocytes was evaluated by reactivity to insulin. In patients with an average size of EAT adipocytes equal to or exceeding the median (87 μm) the percentage of hypertrophic adipocytes was twice as high as in patients in whom the average size of adipocytes was less than 87 μm. This group of patients was also characterized by the higher rate of the Gensini score, lower adiponectin levels, and more severe violation of carbohydrate metabolism. We have revealed direct nonparametric correlation between the size of EAT adipocytes and the Gensini score (rs = 0.56, p = 0.00047). The number of hypertrophic EAT adipocytes showed a direct nonparametric correlation with the Gensini score (rs = 0.6, p = 0.002). Inverse nonparametric correlations were found between the serum adiponectin level and size (rs = −0.60, p = 0.001), hypertrophy of adipocytes (rs = −0.67, p = 0.00), and Gensini score (rs = −0.81, p = 0.00007). An inverse nonparametric correlation was found between the Gensini score and sensitivity of EAT adipocytes to insulin, estimated by the intracellular redox response (rs = −0.90, p = 0.037) and decrease in lipolysis rate upon insulin addition (rs = −0.40, p = 0.05). The intracellular redox response of adipocytes to insulin was directly correlated with fasting insulin and inversely with postprandial insulin. Our data indicate that the size and degree of hypertrophy of the epicardial adipocytes are related to the CAD severity. According to our results, insulin resistance of adipocytes may be considered as one of the factors mediating this relationship.

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