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

Abstract

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.