Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and 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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Roles of the Chemokine System in Development of Obesity, Insulin Resistance, and Cardiovascular Disease

Journal of Immunology Research ◽

10.1155/2014/181450 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 38

Author(s):

Longbiao Yao ◽

Oana Herlea-Pana ◽

Janet Heuser-Baker ◽

Yitong Chen ◽

Jana Barlic-Dicen

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Adipose Tissue ◽

Nutrient Intake ◽

Nutrient Deficiency ◽

Tissue Expansion ◽

Low Grade ◽

Chemokine Production ◽

Increase Risk

The escalating epidemic of obesity has increased the incidence of obesity-induced complications to historically high levels. Adipose tissue is a dynamic energy depot, which stores energy and mobilizes it during nutrient deficiency. Excess nutrient intake resulting in adipose tissue expansion triggers lipid release and aberrant adipokine, cytokine and chemokine production, and signaling that ultimately lead to adipose tissue inflammation, a hallmark of obesity. This low-grade chronic inflammation is thought to link obesity to insulin resistance and the associated comorbidities of metabolic syndrome such as dyslipidemia and hypertension, which increase risk of type 2 diabetes and cardiovascular disease. In this review, we focus on and discuss members of the chemokine system for which there is clear evidence of participation in the development of obesity and obesity-induced pathologies.

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

European Heart Journal ◽

10.1093/eurheartj/ehx502.p1592 ◽

2017 ◽

Vol 38 (suppl_1) ◽

Author(s):

E. Diaz Rodriguez ◽

R.M. Agra ◽

A.L. Fernadez ◽

B. Adrio ◽

J.R. Gonzalez-Juanatey ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Epicardial Adipose Tissue ◽

Protective Mechanisms ◽

Inflammatory Chemokines

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Production and internalization of extracellular vesicules in normal and under conditions of hyperglycemia and insulin resistance

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20216706465 ◽

2021 ◽

Vol 67 (6) ◽

pp. 465-474

Author(s):

N.V. Yunusova ◽

E.E. Dandarova ◽

D.A. Svarovsky ◽

N.S. Denisov ◽

D.N. Kostromitsky ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Endothelial Cells ◽

Adipose Tissue ◽

Diabetic Patients ◽

Clinical Markers ◽

Obesity Epidemic ◽

M1 Polarization ◽

Spherical Structures ◽

Common Group

Extracellular vesicles (EVs) are spherical structures of cell membrane origin, ranging in the size from 40 nm to 5000 nm. They are involved in the horizontal transfer of many proteins and microRNAs. The mechanisms EV internalization include clathrin-dependent endocytosis, caveolin-dependent endocytosis, raft-mediated endocytosis, and macropinocytosis. Type 2 diabetes mellitus (T2DM) is a common group of metabolic disorders in adults; the incidence and prevalence increase in parallel with the obesity epidemic. Since adipose tissue plays a crucial role in the development of insulin resistance, EVs secreted by adipose tissue can be a kind of information transmitter in this process. EVs of adipocytic origin are predominantly absorbed by tissue macrophages, adipocytes themselves, hepatocytes, and skeletal muscles. This contributes to the M1 polarization of macrophages, a decrease in glucose uptake by hepatocytes and myocytes due to the transfer of functionally active microRNAs by these EVs, which affect carbohydrate and lipid metabolism. Patients with T2DM and impaired glucose tolerance have significantly higher levels of CD235a-positive (erythrocyte) EVs, as well as a tendency to increase CD68-positive (leukocyte) and CD62p-positive (platelets/endothelial cells) EVs. The levels of CD31+/CD146-positive BB (endothelial cells) were comparable between diabetic and euglycemic patients. EVs from diabetic patients were preferably internalized by monocytes (mainly classical and intermediate monocyte fractions and to a lesser extent by non-classical monocyte fractions) and B cells compared to euglycemic patients. Internalization of EVs from patients with T2DM by monocytes leads to decreased apoptosis, changes in differentiation, and suppression of reactions controlling oxidative stress in monocytes. Thus, insulin resistance increases secretion of EVs, which are preferentially internalized by monocytes and influence their function. EVs are considered as sources of promising clinical markers of insulin resistance, complications of diabetes mellitus (endothelial dysfunction, retinopathy, nephropathy, neuropathy), and markers of EVs can also be used to monitor the effectiveness of therapy for these complications.

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Relevance of Thoracic Adipose Tissue in Wound Healing Disorder of Diabetic Patients

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0035-1544520 ◽

2015 ◽

Vol 63 (S 01) ◽

Author(s):

J. Andres ◽

C. Dittfeld ◽

A. Jannasch ◽

K. Plötze ◽

T. Waldow ◽

...

Keyword(s):

Wound Healing ◽

Adipose Tissue ◽

Diabetic Patients

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Insulin resistance is localized to skeletal but not heart muscle in type 1 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.5.e756 ◽

1993 ◽

Vol 264 (5) ◽

pp. E756-E762 ◽

Cited By ~ 7

Author(s):

P. Nuutila ◽

J. Knuuti ◽

U. Ruotsalainen ◽

V. A. Koivisto ◽

E. Eronen ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Compartment Model ◽

Normal Subjects ◽

Whole Body ◽

Diabetic Patients ◽

Uptake Rates ◽

Arm Muscles ◽

Type 1 Diabetic Patients

To determine the tissue localization of insulin resistance in type 1 diabetic patients, whole body and regional glucose uptake rates were determined under euglycemic hyperinsulinemic conditions. Leg, arm, and heart glucose uptake rates were measured using positron emission tomography-derived 2-deoxy-2-[18F]-fluoro-D-glucose kinetics and the three-compartment model described by Sokoloff et al. (L. Sokoloff, M. Reivich, C. Kennedy, M.C. DesRosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897–916, 1977) in eight type 1 diabetic patients and eight matched normal subjects. Whole body glucose uptake was quantitated by the euglycemic insulin clamp technique. Whole body glucose uptake was approximately 31% lower in the diabetic patients (P < 0.01) than in the normal subjects, thus confirming the presence of whole body insulin resistance. The rate of glucose uptake was approximately 45% lower in leg muscle when measured in the femoral region (55 +/- 7 vs. 102 +/- 13 mumol.kg muscle-1.min-1, diabetic patients vs. normal subjects, P < 0.05) and approximately 27% lower in the arm muscles (66 +/- 4 vs. 90 +/- 13 mumol.kg muscle-1.min-1, respectively, P < 0.05), whereas no difference was observed in heart glucose uptake [789 +/- 80 vs. 763 +/- 58 mumol.kg muscle-1.min-1 not significant (NS)]. Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.93, P < 0.005) and arm muscles (r = 0.66, P < 0.05) but not with glucose uptake in the heart (r = 0.04, NS). We conclude that insulin resistance in type 1 diabetic patients is localized to skeletal muscle, whereas heart glucose uptake is unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

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My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽

10.1182/blood.v128.22.sci-44.sci-44 ◽

2016 ◽

Vol 128 (22) ◽

pp. SCI-44-SCI-44

Author(s):

Xiaoxia Li

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

Adipose Tissue ◽

Systemic Inflammation ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Inflammatory Diseases ◽

Critical Role ◽

Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

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Adipose Tissue Insulin Resistance is Associated with Macrophage Activation in Non-Diabetic Patients with Non-Alcoholic Fatty Liver Disease

Journal of Hepatology ◽

10.1016/s0168-8278(16)00807-2 ◽

2016 ◽

Vol 64 (2) ◽

pp. S476

Author(s):

C. Rosso ◽

K. Kazankov ◽

M. Gaggini ◽

C. Saponaro ◽

M. Marietti ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Macrophage Activation ◽

Diabetic Patients ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver 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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