Diabetes Mellitus Drives Extracellular Vesicle Secretion and Promotes Increased Internalization by Circulating Leukocytes

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. We designed a longitudinal and cross-sectional cohort of euglycemic, pre-diabetic and diabetic participants. Diabetic individuals had significantly higher levels of EVs in their circulation than euglycemic controls. We found that insulin resistance increases EV secretion through an autophagy-dependent mechanism. Furthermore, the levels of several proteins involved in insulin signaling 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. 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 preferential internalized by leukocytes and whose gene expression is subsequently altered by the internalized EVs. PBMC-derived monocyes were incubated with PBS (control, N=3) or with extracellular vesicles (EVs) from euglycemic (EU, N=3,samples, 1 technical repeat (TR)) or Type 2 diabetes mellitus (T2DM, diabetic, N=2, 2 TR ) individuals.