A negative regulatory role of β-cell-derived exosomes in the glucose-stimulated insulin secretion of recipient β-cells.

Abstract

Exosomes are extracellular vesicles that play a role in intercellular communication through the transportation of their cargo including mRNAs, microRNAs, proteins, and nucleic acids. Exosomes can also regulate glucose homeostasis and insulin secretion under diabetic conditions. However, the role of exosomes in insulin secretion in islet β-cells under physiological conditions remains to be clarified. The aim of this study was to investigate whether exosomes derived from pancreatic islet β-cells could affect insulin secretion in naïve β-cells. We first confirmed that exosomes derived from the RIN-m5f β-cell line interfered with the glucose-stimulated insulin secretion (GSIS) of recipient β-cells without affecting cell viability. The exosomes significantly reduced the protein expression levels of phosphorylated Akt, phosphorylated GSK3α/β, CaMKII, and GLUT2 (insulin-related signaling molecules), and they increased the protein expression levels of phosphorylated NFκB-p65 and Cox-2 (inflammation-related signaling molecules), as determined by a Western blot analysis. A bioinformatics analysis of Next-Generation Sequencing data suggested that exosome-carried microRNAs, such as miR-1224, -122-5p, -133a-3p, -10b-5p, and -423-5p, may affect GSIS in recipient β-cells. Taken together, these findings suggest that β-cell-derived exosomes may upregulate exosomal microRNA-associated signals to dysregulate glucose-stimulated insulin secretion in naïve β-cells.