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

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.

scholarly journals Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability

2017 ◽  
Vol 114 (2) ◽  
pp. 336-346 ◽  
Author(s):  
Esther Díaz-Rodríguez ◽  
Rosa M Agra ◽  
Ángel L Fernández ◽  
Belén Adrio ◽  
Tomás García-Caballero ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Wound Healing ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Epicardial Adipose Tissue ◽  
Diabetic Patients ◽  
Chemokine Production ◽  
Inflammatory Chemokines

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.

Abstract 18673: JNK Inhibition Restores Endothelial Function in Type 2 Diabetes Mellitus

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Rosa Breton-Romero ◽  
Bihua Feng ◽  
Monika Holbrook ◽  
Melissa G Farb ◽  
Jessica L Fetterman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Diabetic Patients ◽  
Jnk Activation

Introduction: Diabetes mellitus type 2 is an increasingly public health problem and it is a major cause in the development of cardiovascular diseases. Endothelial dysfunction is a key mechanism that contributes to the pathogenesis of cardiovascular diseases and is a well-known feature of clinical diabetes. Prior studies have demonstrated an impaired nitric oxide bioavailability and a reduced endothelium-dependent vasodilation under diabetic conditions and in animal models, JNK activity has been widely described to be involved in systemic insulin resistance. Hypothesis: Our study aimed to evaluate the involvement of JNK in endothelial dysfunction, studying its potential role in altered eNOS activation and NO synthesis in diabetic patients. Methods: We measured endothelial function and JNK activity in freshly isolated endothelial cells from diabetic patients (n=38) and nondiabetic controls (n=40). Results: ECs from diabetic patients displayed impaired eNOS activation and reduced NO release after insulin and A23187 stimulation, consistent with the presence of endothelial dysfunction. JNK activation was higher in diabetic (**P=0.003), and was associated with lower flow-mediated dilation (r=-0.53, *P=0.02). In endothelial cells from diabetic patients, treatment with JNK chemical inhibitor (SP600125) restored eNOS activation and insulin response (***P<0.001). Nitric oxide bioactivity after A23187 stimuli with diabetes was also recovered in endothelial cells from patients with diabetes. Conclusions: In summary, our data suggest that JNK activation contributes to vascular insulin resistance and endothelial dysfunction in patients with type 2 diabetes and may represent a target in novel therapeutic opportunities.

scholarly journals Clinical Investigations: Correlations Between Human Somatotype Components And Some Anthropometric Parameters In Male Patients With Type 2 Diabetes Mellitus

Folia Medica ◽  
2014 ◽  
Vol 56 (3) ◽  
pp. 175-181
Author(s):  
Atanas G. Baltadjiev ◽  
Stefka V. Vladeva
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Adipose Tissue ◽  
Anthropometric Measurements ◽  
Diabetic Patients ◽  
Strong Positive Correlation ◽  
Positive Correlation ◽  
Male Patients

ABSTRACT The AIM of the present study was to find and compare the correlations between somatotype and some anthropological parameters in Bulgarian male patients with type 2 diabetes mellitus. PATIENTS AND METHODS: Anthropometric measurements were taken from 165 male patients with type 2 diabetes mellitus. All patients were ethnic Bulgarians. They were divided into two age groups: a 40-60-year group (58 patients, mean age 52.05 ± 0.73 yrs), and a 61-80-year group (111 patients, mean age 68.02 ± 0.53 yrs). The controls were allocated into similar agematched groups. Direct anthropometric measurements were body height and weight, biepicondylar breadth of the humerus and biepicondylar breadth of the femur. Circumferential measurements were taken from the relaxed and contracted upper arm, the forearm, the waist, the hip, the thigh and the medial calf. Skin folds were measured below the inferior angle of the scapula, above the X rib, above the crista iliaca, at the abdomen, triceps brachii, forearm, thigh and the medial calf. The components of human somatotype according to the criteria of Heath-Carter, body mass index (ВМІ) and waist-to-hip ratio (WHR) were calculated. RESULTS: We found very strong positive correlations (РС > 0.70) between ВМI and the endomorphic and mesomorphic components of somatotype in 40-60-year-old male diabetic patients. The correlation between the endomorphic and mesomorphic components of somatotype and the anthropometric measurements characterizing the central accumulation of adipose tissue (waist circumference, hip circumference, WHR) was very strong positive (РС = 0.5-0.7). Male diabetic patients aged 61-80 years: we found a very strong positive correlation between endomorphic and mesomorphic components and ВМІ, a strong correlation between these components and the waist circumference, and a good correlation between the components and the circumferences of the waist and hip and WHR. CONCLUSIONS: In male patients with type 2 diabetes aged 40-60 years, the endomorphic and mesomorphic components of somatotype are strongly positively correlated with the parameters which characterize the total adipose tissue accumulation in the human body (ВМІ). There is a good positive correlation between the two components of somatotype and the parameters showing visceral adipose tissue accumulation (circumferences of waist, hip, thigh and WHR). In male patients with type 2 diabetes aged 61-80 years we found a strong positive correlation of the endomorphic and mesomorphic components of somatotype with BMI and a good positive correlation with the circumferences of the waist, hip, thigh and WHR.

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

Blood ◽  
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.

scholarly journals The effect of obesity and Insulin Resistance on Liver Enzymes in Type2 Diabetes Mellitus

2015 ◽  
Vol 12 (3) ◽  
pp. 536-545
Author(s):  
Baghdad Science Journal
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Alkaline Phosphatase ◽  
Negative Correlation ◽  
Liver Enzymes ◽  
Alanine Transaminase ◽  
Obese Group ◽  
Control Group ◽  
Diabetic Patients ◽  
And Control

Diabetes mellitus (DM) has been defined as a clinical syndrome that is characterized by abnormal carbohydrate metabolism. The chronic hyperglycemia of diabetes is associated with long term damage, dysfunction, and failure of different organs, especially the liver .This study was conducted to assess the effect obesity and insulin resistance on liver enzymes in diabetic Iraqi patients.A comparative study of (90) Iraqi adults divided to three subgroup(30) obese ,(30) nonobese diabetic patients and(30)person had used as control. The analysis included Liver enzyme ALP,ALT,AST,GGT ,Fasting Plasma Glucose (FBG) , Lipid Profile , Hemoglobin A1C , insulin and homeostasis model assessment of insulin resistance (HOMA IR) were measured. Subjects were excluded from this study if they had liver disease, alcohol intake, medications for lowering lipid, insulin treatment, pregnant women and women taking contraceptive pills . The study shows significantly higher of liver enzymes level ( gamma glutamyl transpeptidase (GGT), alkaline phosphatase, Aspartate Amino Transferase , Alanine Transaminase) in obese diabetic patients compared with non-obese diabetic patients and control subject and HOMA IR showed significantly higher in obese diabetic patients compared with non-obese with diabetic patients and control (P < 0.05). The lipids level showed significantly higher in obese diabetic patients compared with non-obese diabetic patients and control.The HbA1c level showed higher significantly in obese diabetic patients compared with control and ther is a posative correlation between insulin and HOMA IR , ALP in obeses diabetic patients while there was negative correlation between ALT and cholesterol in obese group and with HbA1c in control group. The liver enzymes level of(alkaline phosphatase, alanine transaminase, aspartate transaminase gama glutaminase transferase ) is significantly higher in obese diabetic patients than non –obese diabetic patients and control group , also There was posative correlation between ALP and HOMA IR while there was negative correlation between ALT and cholesterol in obese group and with HbA1c in control group .

ErbB2 Expression on Left Ventricular Epicardial Endothelial Cells and CD105+ Cells is Decreased in Patients with Diabetes Mellitus.

2021 ◽  
Author(s):  
Joanne T. deKay ◽  
Joshua Carver ◽  
Bailey Shevenell ◽  
Angela M. Kosta ◽  
Sergey Tsibulnikov ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Cell Surface ◽  
High Glucose ◽  
Artery Bypass ◽  
Surface Expression ◽  
Left Ventricular ◽  
Cell Surface Expression ◽  
Erbb Receptors ◽  
Diabetic Patients

Abstract Background We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105+ cells obtained from cardiac biopsies of patients undergoing coronary artery bypass grafting surgery (CABG). Methods Endothelial cells and CD105+ non-endothelial cells were freshly isolated from LV epicardial biopsies obtained from 15 subjects with diabetes mellitus (DM) and 8 controls. The expression of ErbB recepotrs was examined using multiparametric flow cytometry. Human microvascular endothelial cells (HMEC-1) and LV epicardial CD105+ non-endothelial cells were used to determine the effect of high glucose on ADAM10-dependent cleavage of ErbB receptors. Results We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2 on both endothelial cells and CD105+ non-endothelial cells. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high glucose in HMEC-1 and LV epicardial CD105+ non-endothelial cells, using a novel flow cytometric approach to simultaneously determine the total level, cell surface expression, and phosphorylation of ErbB2. Incubation of cells in the presence of 25 mM D-glucose resulted in decreased cell surface expression of ErbB2. We also found high expression of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) on both endothelial cells and CD105+ non-endothelial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. Conclusions We suggest that high glucose depresses ErbB receptor signaling in endothelial cells and cardiac progenitor cells via the promotion of ADAM10-dependent cleavage of ErbB2 at the cell surface, thus contributing to vascular dysfunction and adverse remodeling seen in diabetic patients.

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