Diabetes mellitus drives extracellular vesicle secretion and promotes increased internalization by circulating leukocytes

Background: The rising incidence of diabetes mellitus represents an important global challenge. Type 2 diabetes is a chronic degenerative metabolic disease that is characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance. Accumulating data suggest that circulating factors may contribute to numerous diseases, including diabetes. Intriguing data from mouse models and in vitro cell culture indicate that extracellular vesicles (EVs) may be important in diabetes through altering insulin signalling. Methods: We isolated plasma EVs from cross-sectional and longitudinal cohorts of euglycemic, pre-diabetic and diabetic participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span study. We tested the effects of insulin resistance on EVs using primary neurons and measured EV internalization as well as gene expression in human leukocytes. Results: Individuals with diabetes had significantly higher levels of circulating EVs than euglycemic controls. Using primary cortical neurons, we observed that insulin resistance increases EV concentration through modulating the autophagy pathway. Furthermore, using a proteomic approach, we examined the expression of EV proteins involved in insulin signalling and inflammation. We found alterations in EV protein levels in individuals with high levels of insulin resistance and ßcell dysfUnction. Using an assay to measure EV internalization, we discovered that EVs from diabetic individuals were preferentially internalized and influenced gene expression in circulating leukocytes. EVs from diabetic individuals affected cellular pathways related to cell survival, oxidative stress and immune function. Summary/conclusion: Our data indicate that insulin resistance promotes EV secretion and affects the internalization of EVs by circulating leukocytes. This knowledge may further our understanding of the pathophysiological role of EVs in diabetes and might facilitate development of novel diagnostic and therapeutic approaches. In addition, this work furthers our insight into the contribution of EVs to age-related disease.