Altered Extracellular Vesicle Concentration, Cargo, and Function in Diabetes

Abstract

Type 2 diabetes is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs) (exosomes, microvesicles, and apoptotic bodies) are small (30-400 nm) lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. Here, we designed cross-sectional and longitudinal cohorts of euglycemic participants and participants with prediabetes or diabetes. Individuals with diabetes had significantly higher levels of EVs in their circulation than euglycemic control participants. Using a cell-specific EV assay, we identified that levels of erythrocyte-derived EVs are higher with diabetes. We found that insulin resistance increases EV secretion. Furthermore, the levels of insulin signaling proteins were altered in EVs from individuals with high levels of insulin resistance and β-cell dysfunction. Moreover, EVs from individuals with diabetes were preferentially internalized by circulating leukocytes. Cytokine levels in the media and in EVs were higher from monocytes incubated with diabetic EVs. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress, and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferentially internalized by leukocytes, and alters leukocyte function.

Exosomes or Microvesicles, a Secreted Subcellular Organelle Contributing to Inflammation and Diabetes

“…Several of their findings were somewhat expected and actually served as a validation of published findings using in vitro systems. For example, they noted that the numbers of exosomes in the plasma correlated with disease severity (11). This has been observed in previous studies of diabetes (12,13).…”

“…The study by Freeman et al (11) in this issue of Diabetes is unique in that it uses an ex vivo approach to study the role and mechanism of action of EVs derived from blood plasma of normal patients, patients with prediabetes, and patients with diabetes in the development of disease (11). The availability of plasma EVs from cohorts of individuals at two time points, separated by 5 years, allowed monitoring of changes associated with disease progression, since it was possible to compare individuals without diabetes with those who progressed to overt diabetes.…”

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

“…Previous research determined that type 2 diabetes alters the levels of exosomal insulin signaling proteins in circulation. Afterward, altered exosomes will preferentially shape the physiological functions of circulating leukocytes via target internalization . Recently, adipocyte‐derived exosomes have been regarded as a novel therapy target to control metabolic disorders and inflammatory responses in various organs/tissues during obesity .…”

“…Afterward, altered exosomes will preferentially shape the physiological functions of circulating leukocytes via target internalization. 43 Recently, adipocyte-derived exosomes have been regarded as a novel therapy target to control metabolic disorders and inflammatory responses in various organs/tissues during obesity. 13,44 Based on these observations, we hypothesize that adipocyte-derived exosomes may exert special induced and inhibitory effects on hepatic steatosis.…”

Adipose‐derived exosomes: A novel adipokine in obesity‐associated diabetes

“…Exosomal protein and micro RNA (miRNA) profiles were altered from those of healthy individuals, rendering specific exosome cargos the possibility of being the serum biomarkers for T2DM (Santovito et al, 2014; H. Zhang et al, 2018). For example, the proteins related to insulin signalings, such as the phospho-insulin receptor and leptin receptor, were decreased in serum exosomes from diabetic individuals (Freeman et al, 2018). Exosomal miR-27a and miR-320 were dysregulated in patients with T2DM (Karolina et al, 2012).…”