Abstract
The metabolic syndrome (MetS) is characterized by the association of several disorders that increase the risk of developing cardiovascular diseases and insulin resistance. In addition to the development of type II diabetes, insulin resistance can also lead to many complications such as atherosclerosis, dyslipidemia and high blood pressure. Extracellular vesicles (EVs), including microvesicles (MVs) and exosomes can be considered as new biomarkers of different pathologies, and can be involved in intercellular communication. We hypothesize that EVs could be implicated in MetS-associated insulin resistance in human endothelial cells and hepatocytes. MVs and exosomes were isolated from plasma of non-MetS and MetS patients by serial centrifugation. Then, human aortic endothelial cells (HAoECs) and human hepatocytes (HepG2) were treated with EVs or palmitic acid for 24 hours, before stimulation with 100nM insulin for 5 minutes. Finally, we studied insulin signaling pathway by analyzing specific phosphorylated proteins: IRS1 at Tyr612, AKT at Ser473 and GSK3β at Ser9. Neither MVs nor exosomes from nMetS and MetS patients significantly modified the capacity of insulin to induce activation of AKT pathway. Also, no effect was observed when HepG2 were treated with MVs. In contrast, exosomes from MetS, but not those from nMetS patients, were able to decrease significantly the insulin-induced phosphorylation of AKT and GSK3β, in HepG2 cells without affecting IRS1 phosphorylation. These results provide evidence: – of the specificity of the effects of exosomes regarding the hepatocytes but not the endothelial cells and; – that exosomes, but not MVs, from MetS patients may contribute to the insulin resistance in hepatocytes, by impairing the AKT- GSK3β pathway in response to insulin.
Published Version
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