Extracellular Vesicles and Insulin Resistance: A Potential Interaction in Vascular Dysfunction

Insulin resistance plays a key role in cardiovascular complications associated with diabetes mellitus and hypertensive disorders. In states of insulin resistance several circulating factors may contribute to a defective insulin sensitivity in different tissues, including the vasculature. One of these factors influencing the vascular insulin resistance are the extracellular vesicles. The extracellular vesicles include exosomes, microvesicles, and apoptotic bodies which are released to the circulation by different vascular cells. Since the cargo of extracellular vesicles seems to be altered in metabolic complications associated with insulin resistance, these vesicles may be candidates contributing to vascular insulin resistance. Despite the studies linking insulin resistance signalling pathways with the vascular effect of extracellular vesicles, the involvement of these structures in vascular insulin resistance is a phenomenon that remains unclear.

Download Full-text

Endothelial dysfunction in insulin-resistant rats is associated with oxidative stress and COX pathway dysregulation

Physiological Research ◽

10.33549/physiolres.931583 ◽

2009 ◽

pp. 499-509

Author(s):

A Oudot ◽

D Behr-Roussel ◽

S Compagnie ◽

S Caisey ◽

O Le Coz ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Vascular Dysfunction ◽

Pressor Response ◽

In Vitro Study ◽

Cardiovascular Complications ◽

Insulin Resistant ◽

Pathway Dysregulation

Because insulin resistance is inevitably associated with cardiovascular complications, there is a need to further investigate the potential involvement of oxidative stress and the cyclo-oxygenase (COX) pathway in the vascular modifications associated to this pathological context. Endothelial function was evaluated in control and fructose-fed rats (FFR) by i) in vitro study of endothelium-dependent and -independent relaxations of aortic rings, and ii) in vivo telemetric evaluation of pressor response to norepinephrine. After 9 weeks of diet, FFR displayed hypertriglyceridemia, hyperinsulinemia and exaggerated response to glucose overload. Aortic rings from control rats and FFR exhibited comparable endothelium-dependent relaxations to Ach. In the presence of indomethacin, relaxations were significantly reduced. FFR showed exaggerated pressor responses to norepinephrine that were abolished with indomethacin. Urinary nitrites/nitrates, 8-isoprostanes and thromboxane B2 excretion levels were markedly enhanced in FFR, whereas the plasma levels of 6-keto prostaglandin F1α were unchanged. In conclusion, fructose overload in rats induced hypertriglyceridemia and insulin resistance associated with an enhanced oxidative stress. This was associated with COX pathway dysregulation which could be one of the contributors to subsequent vascular dysfunction. Consequently, reduction of oxidative stress and regulation of the COX pathway could represent new potential therapeutic strategies to limit vascular dysfunction and subsequent cardiovascular complications associated with insulin resistance.

Download Full-text

The emerging roles of extracellular vesicles in ovarian cancer

Current Drug Metabolism ◽

10.2174/1389200221666201110155721 ◽

2020 ◽

Vol 21 ◽

Author(s):

Yin-xue Wang ◽

Yi-xiang Wang ◽

Yi-ke Li ◽

Shi-yan Tu ◽

Yi-qing Wang

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Large Scale ◽

Current Treatment ◽

Detection Methods ◽

Drug Resistant ◽

Apoptotic Bodies ◽

Biological Mechanisms ◽

Gynecological Malignancy ◽

Resistance To Chemotherapy

: Ovarian cancer (OC) is one of the deadliest gynecological malignancy. Epithelial ovarian cancer (EOC) is its most common form. OC has both a poor prognosis and a high mortality rate due to the difficulties of early diagnosis, the limitation of current treatment and resistance to chemotherapy. Extracellular vesicles is a heterogeneous group of cellderived submicron vesicles which can be detected in body fluids, and it can be classified into three main types including exosomes, micro-vesicles, and apoptotic bodies. Cancer cells can produce more EVs than healthy cells. Moreover, the contents of these EVs have been found distinct from each other. It has been considered that EVs shedding from tumor cells may be implicated in clinical applications. Such as a tool for tumor diagnosis, prognosis and potential treatment of certain cancers. In this review, we provide a brief description of EVs in diagnosis, prognosis, treatment, drug-resistant of OC. Cancer-related EVs show powerful influences on tumors by various biological mechanisms. However, the contents mentioned above remain in the laboratory stage and there is a lack of large-scale clinical trials, and the maturity of the purification and detection methods is a constraint. In addition, amplification of oncogenes on ecDNA is remarkably prevalent in cancer, it may be possible that ecDNA can be encapsulated in EVs and thus detected by us. In summary, much more research on EVs needs to be perform to reveal breakthroughs in OC and to accelerate the process of its application on clinic.

Download Full-text

Anti-obesity effects of Grifola frondosa through the modulation of lipid metabolism via ceramide in mice fed a high-fat diet

Food & Function ◽

10.1039/d1fo00666e ◽

2021 ◽

Author(s):

Xue Jiang ◽

Jie Hao ◽

Zijian Liu ◽

Xueting Ma ◽

Yuxin Feng ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

High Fat Diet ◽

Fat Deposition ◽

Grifola Frondosa ◽

High Fat ◽

Metabolic Complications ◽

Basidiomycete Fungus

Obesity is characterized by massive fat deposition and is related to a series of metabolic complications, such as insulin resistance (IR) and steatohepatitis. Grifola frondosa (GF) is a basidiomycete fungus...

Download Full-text

A Study on the Factors influencing insulin resistance in obese adolescents

Journal of Nanjing Medical University ◽

10.1016/s1007-4376(09)60014-9 ◽

2008 ◽

Vol 22 (6) ◽

pp. 391-394

Author(s):

Yongmei Jin ◽

Pengfei Dou

Keyword(s):

Insulin Resistance ◽

Obese Adolescents ◽

Factors Influencing

Download Full-text

Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

Clinical Science ◽

10.1042/cs20080550 ◽

2009 ◽

Vol 117 (3) ◽

pp. 129-138 ◽

Cited By ~ 32

Author(s):

Emily M. Segar ◽

Andrew W. Norris ◽

Jian-Rong Yao ◽

Shanming Hu ◽

Stacia L. Koppenhafer ◽

...

Keyword(s):

Insulin Resistance ◽

Vascular Function ◽

Vascular Dysfunction ◽

Diabetic Rats ◽

Late Gestation ◽

Group Differences ◽

Pregnant Rats ◽

Increased Risk ◽

Specific Insulin ◽

Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

Download Full-text

Abstract 177: Promotion Of Nitroso-redox Balance By Beta 3 Adrenoceptor Agonism: Therapeutic Implications For Cardiovascular Complications Of Diabetes

Circulation Research ◽

10.1161/res.115.suppl_1.177 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Keyvan Karimi Galougahi ◽

Chia-chi Liu ◽

Alvaro Garcia ◽

Natasha A Fry ◽

Clare L Hawkins ◽

...

Keyword(s):

Nadph Oxidase ◽

Cardiac Myocytes ◽

Vascular Dysfunction ◽

Pump Current ◽

Redox Balance ◽

Cardiovascular Complications ◽

Oxidative Modification ◽

Oxidation Products ◽

Therapeutic Implications ◽

Endothelial Nitric Oxide

Rationale: Disrupted balance between NO and O2.- is central in pathobiology of diabetes-induced cardiomyopathy and vascular dysfunction. We examined if stimulation of β3 adrenergic receptors (β3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re-establish NO/O2.- balance, relieve oxidative inhibition of key caveolar proteins and protect against diabetes-induced cardiovascular dysfunction. Methods/Results: A hyperglycemic, hyperinsulinemic state was established in male White New Zealand rabbits by infusion of the insulin receptor antagonist S961 (12 μg/kg/h). Diabetes induced NADPH oxidase-dependent glutathionylation (GSS-) of the caveolar proteins Na+-K+ pump’s β1 subunit and eNOS in cardiac myocytes and aorta, an oxidative modification that inhibits the pump and uncouples eNOS. Consistent with this, diabetes was associated with reduced electrogenic Na+-K+ pump current in voltage-clamped cardiac myocytes and impaired endothelium-dependent vasorelaxation. Selective β3 AR agonist CL316243 (CL, 40 μg/kg/h) restored NO levels analysed by spin-trapping of NO-Fe(DETC)2 complexes; decreased diabetes-induced elevation in O2.- measured by HPLC analysis of dihydroethidium oxidation products, improved endothelium-dependent vasorelaxation, and restored the Na+-K+ pump function in cardiac myocytes. These effects were mediated by CL abolishing diabetes-induced increase in eNOS-GSS and β1-GSS through a decrease in forward reaction rate for glutathionylation by suppressing diabetes-induced NADPH oxidase activation, which was further amplified by promotion of de-glutathionylation via enhancement in association of glutaredoxine-1, the enzyme catalysing de-glutathionylation, with eNOS and Na+-K+ pump. Conclusion: β3 AR activation re-established nitroso-redox balance and relieved oxidative inhibition of key caveolar proteins in diabetes. β3 AR agonists are promising in treatment of diabetes-induced cardiovascular complications.

Download Full-text

Inflammation and impaired adipogenesis in hypertrophic obesity in man

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00377.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E999-E1003 ◽

Cited By ~ 162

Author(s):

Birgit Gustafson ◽

Silvia Gogg ◽

Shahram Hedjazifar ◽

Lachmi Jenndahl ◽

Ann Hammarstedt ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Molecular Mechanisms ◽

Whole Body ◽

Preadipocyte Differentiation ◽

Metabolic Complications ◽

Adipose Cell ◽

Subcutaneous Adipose ◽

Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

Download Full-text

Mesenchymal stem cells versus their extracellular vesicles in treatment of liver fibrosis: Is it possible to compare?

Medical Research Archives ◽

10.18103/mra.v9i2.2318 ◽

2021 ◽

Vol 9 (2) ◽

Author(s):

Noha Attia ◽

Yasmine Khalifa ◽

Dina Rostom ◽

Mohamed Mashal

Keyword(s):

Liver Fibrosis ◽

Extracellular Vesicles ◽

Therapeutic Strategy ◽

Secretory Proteins ◽

Apoptotic Bodies ◽

Limited Evidence ◽

In Vivo Models ◽

Dose Determination

Liver fibrosis (LF) is a worldwide health problem that is associated with a range of complications and high mortality. Due to the scarcity of liver donors, mesenchymal stem cell (MSC) therapy emerged as an alternative therapeutic strategy. However, it is widely accepted that most of the transplanted MSCs exhibit their therapeutic impact mainly via a bystander paracrine (medicinal) capacity. In addition to their secretory proteins, MSCs also produce various types of extracellular vesicles (EVs) that are classiﬁed into three main subtypes: microvesicles, exosomes and apoptotic bodies. Thanks to their peculiar cargo composition (e.g., proteins, lipids, and nucleic acids), EVs serve as an advantageous candidate for cell-free therapy. Recently, MSC-derived EVs (MSC-EVs) have gained the podium due to their regenerative and immunomodulatory effect. In mitigation/treatment of LF, a plethora of recent studies have shown the anti-inflammatory, anti-fibrotic and cytoprotective effects of both MSCs and MSC-EVs in various in vitro and in vivo models of LF. However, despite the limited evidence, we sought in this mini review to sort out the established data and formulate several challenging questions that must be answered to pave the way for further clinical applications. One of the major questions to ask is “Which is the best therapeutic approach, MSCs or MSC-EVs?” We tried to highlight how difficult it might be to compare the two approaches while our understanding of both candidates is still deficient. Among the major obstacles against such comparison is the inaccurate equivalent dose determination, the unknown in vivo behavior, and the undetermined lifespan/fate of each. Currently, the fields of MSCs and MSC-EVs seem to be rich in ideas but lacking in appropriate technologies to test these ideas. Nevertheless, continuous efforts are likely to help resolve some of the challenges listed here.

Download Full-text

First trimester gut microbiome induces Inflammation-dependent gestational diabetes phenotype in mice

10.1101/2021.09.17.21262268 ◽

2021 ◽

Author(s):

Yishay Pinto ◽

Sigal Frishman ◽

Sondra Turjeman ◽

Adi Eshel ◽

Meital Nuriel-Ohayon ◽

...

Keyword(s):

Insulin Resistance ◽

Gestational Diabetes ◽

Gut Microbiome ◽

First Trimester ◽

Microbial Composition ◽

Metabolic Complications ◽

Wide Range ◽

First Trimester Of Pregnancy ◽

Stool Samples ◽

Clinical Records

AbstractGestational diabetes mellitus (GDM) is a condition in which non-diabetic women are diagnosed with glucose intolerance during pregnancy, typically in the second trimester. GDM can lead to a wide range of obstetrical and metabolic complications for both mother and neonate1. Early identification of GDM risk, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing GDM incidence, as well as its associated short and long term morbidities2. Here, we comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy. We found elevated levels of proinflammatory serum cytokines in those who later developed GDM. The women’s stool samples were also characterized by decreased levels of several fecal short-chain fatty acids and altered microbiome. We next tested the hypothesis that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin-resistance. Stool samples collected early in pregnancy from women from three populations who did and did not later develop GDM were transplanted to germ-free mice and confirmed that both inflammation and insulin-resistance are induced by the microbiome of pregnant women more than 10 weeks prior to GDM diagnosis. Following these observations, we used a machine-learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers. Our model showed high predictive accuracy. Overall, our results suggest that the gut microbiome of women in the first trimester plays a remarkable role in inflammation-induced GDM pathogenesis and point to dozens of GDM markers during the first trimester of pregnancy, some of which may be targets for therapeutic intervention.

Download Full-text