Localization and function of multivesicular-bodies that release exosomes in islet cells: dysregulation during type-2 diabetes

Abstract

Type-2 diabetes (T2D) is characterized by high blood glucose due to compromised insulin secretion from pancreatic beta-cells. Beta-cells primarily comprise insulin-secreting large-dense-core-vesicles/insulin-secretory-granules (ISGs) and also multivesicular-bodies (MVBs). MVBs are vesicles of endosomal origin containing intraluminal vesicles, which upon fusion with the plasma membrane, secrete exosomes. These play a significant role in the physiology and pathology of T2D via intercellular communication. The role of MVBs and their influence on ISGs of beta-cells or their characterization is yet to be uncovered. In our study, we characterized the role of MVBs by comparing them to largely well-characterized ISGs in beta-cells. We compared the density, localization, and exocytosis of MVBs with ISGs in beta-cells. For this, we developed a novel probe where we exploit the efficiency of tetraspanins CD63 and CD151 to label the MVBs in beta-cells. We showed that the beta-cells have a significantly higher density of ISGs than MVBs. MVBs and ISGs are spatially localized apart within beta-cells. The proteins that localize with MVBs are different from the ones that localize with ISGs. Exocytosis of ISGs occurs at the periphery of the beta-cells and takes significantly lesser time when compared to exosome release, which is non-peripheral and takes a longer duration. Further, we also observed a significant reduction in the density of ISGs and MVBs in T2D patients' islets compared to healthy controls. Studying the effect of MVBs on insulin secretion in physiological and T2D conditions has huge potential. This study provides a strong basis to open new avenues for such future studies.