Comparison of localization and release of multivesicular bodies and secretory granules in islet cells: Dysregulation during type‐2 diabetes

Abstract

Abstract Multivesicular bodies (MVBs) are vesicles of endosomal origin containing intraluminal vesicles, which upon fusion with plasma membrane, secrete exosomes. They play a significant role in the physiology and pathology of type‐2 diabetes (T2D) due to disrupted intercellular communication. The role of MVBs and their influence on insulin secretory granules (ISGs) of β‐cells or their characterization is yet to be uncovered. In our study, we compared MVBs to largely well‐characterized ISGs in β‐cells. This study compares the density, localization, and exocytosis of CD63+ compartments (CD63+c) with NPY labelled ISGs (NISGs) in β‐cells. For this, tetraspanin CD63 was exploited to majorly label MVBs in β‐cells. These labels preserve the structural integrity of labelled compartments and mostly do not localize with other endo‐lysosomal compartments. This study showed that the β‐cells have a significantly higher density of NISGs than CD63+c. CD63+c and NISGs are spatially localized apart within β‐cells. The proteins that localize with CD63+c are different from the ones that localize with NISGs. Exocytosis of NISGs occurs at the periphery of the β‐cells and takes significantly less time when compared to the release of CD63+c, which is non‐peripheral and takes a longer duration. Mechanistically, the availability of CD63+c for exocytosis was assessed and found that an equilibrium is maintained between docking and undocking states at the plasma membrane. Although there are a high number of short‐term residing, visiting CD63+c at the plasma membrane, the availability of CD63+c for exocytosis is maintained due to docking and undocking states. Further, a significant reduction in the density of NISGs and CD63+c was observed in β‐cells isolated from T2D donors compared to healthy counterparts. 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.

Keywords

• Pancreatic beta-cells
• Exocytosis
• Membrane trafficking
• Metabolism