Abstract
Beta-cell (β-cell) injury is the hallmark of autoimmune diabetes. However, the mechanisms by which autoreactive responses are generated in susceptible individuals are not well understood. Extracellular vesicles (EV) are produced by mammalian cells under normal and stressed physiological states. They are an important part of cellular communication, and may serve a role in antigen processing and presentation. We hypothesized that isolated human islets in culture produce EV that contain diabetes autoantigens (DAA) from these otherwise normal, non-diabetic donors. Here we report the caspase-independent production of EV by human islets in culture, and the characterization of DAA glutamic acid decarboxylase 65 (GAD65) and zinc transporter 8 (ZnT8), as well as the β-cell resident glucose transporter 2 (Glut2), present within the EV.
Highlights
An underlying hallmark of type 1 diabetes (T1DM) is the direct injury to the insulin-producing β-cells within the islets of Langerhans
Our study focused on determining whether human islet-derived Extracellular vesicles (EV) harbor known diabetes autoantigens (DAA)
We report the production of EV by normal, nondiabetic human islets following isolation, their characterization using flow cytometry and proteomic-based approaches, and the observation of T1DM autoantigens in these extracellular particles (Fig. 1)
Summary
An underlying hallmark of type 1 diabetes (T1DM) is the direct injury to the insulin-producing β-cells within the islets of Langerhans. The detection of at least two AAb in asymptomatic individuals is defined as presymptomatic normoglycemia, a state which carries 5-year and 10-year risks of 44 and 70%, respectively, in progressing to overt diabetes[6]. The development of insulitis, β-cell injury, and AAb have been extensively studied, the factors or signals which initiate this process are not known. Our study focused on determining whether human islet-derived EV harbor known diabetes autoantigens (DAA). We report the production of EV by normal, nondiabetic human islets following isolation, their characterization using flow cytometry and proteomic-based approaches, and the observation of T1DM autoantigens in these extracellular particles (Fig. 1)
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