The presence of a proinflammatory islet microenviroment and consequent dysregulation of glucose-stimulated insulin secretion (GSIS) is a hallmark feature of both type 1 and type 2 diabetes. Recent evidence has implicated islet cell-derived extracellular vesicles (EVs) as novel mediators of cytokine-derived inflammatory stress in diabetes, however the mechanisms governing this process remain largely unknown. Therefore, we set out to test the hypothesis that cytokine-mediated β-cell dysfunction is mediated in part through β-cell autocrine release of proinflammatory EVs which promote inflammation and inhibit GSIS. Particle size analysis of EVs from conditioned media of cytokine treated (IL-1β, TNF-α, and IFNγ) Min6 β-cells (CytoEV) showed an overall increase in β-cell EV secretion (∼2 fold increase, P<0.05) and a decrease in the average size of secreted EVs (P<0.05) implicating a shift towards a more exosomal EV profile. Subsequently, functional assessment of isolated mouse islets treated (48h) with CytoEVs resulted in a significant suppression of GSIS (∼80%, P<0.05 vs. control). Moreover, acute exposure to CytoEVs also recapitulated the transcriptional signature of β-cell failure in diabetes characterized by increased expression of key proinflammatory genes (e.g., Cxcl10, Tlr1, Tlr4), and a decrease in Insulin and Pdx-1 expression (∼40%, P<0.05 for CytoEVs vs. control). Finally, proteomics analysis of CytoEVs from Min6 and INS-1 832/13 lines (compared to control EVs from each line) revealed a distinct proinflammatory profile consisting of proteins implicated in type 1 diabetes and dendritic cell maturation pathways (e.g., HLA-A, STAT1, INS, CPE etc., P<0.05). Taken together, this work provides a novel mechanism of β-cell dysfunction in diabetes mediated by the autocrine exchange of proinflammatory EVs which has implications for the detection and treatment of β-cell failure in diabetes.


N. Javeed: None. T.K. Her: None. P.M. Vanderboom: None. I.R. Lanza: None. A. Matveyenko: None.

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