Altered Extracellular Vesicle Concentration, Cargo and Function in Diabetes Mellitus

Type 2 diabetes mellitus 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 (50-400 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, pre-diabetic and diabetic participants. Diabetic individuals had significantly higher levels of EVs in their circulation than euglycemic controls. Using a cell-specific EV assay, we identified that erythrocyte-derived EVs are higher with diabetes. We found that insulin resistance increases EV secretion. Furthermore, the levels insulin signaling proteins were altered in EVs from individuals with high levels of insulin resistance and β-cell dysfunction. Moreover, EVs from diabetic individuals 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.