Extracellular Vesicles: Biology, Intercellular Communication and Therapeutic Potential in Diabetes

ABSTRACT Diabetes mellitus is a complex metabolic disorder affecting millions of people worldwide. Several studies have demonstrated significant alterations in the levels of small effector molecules such as TGFB, Wnt ligands, and sets of noncoding RNAs in diabetic conditions. These small molecules and non‐coding RNAs are released into the extracellular space through extracellular vesicles (EVs). Therefore, EVs offer an exciting opportunity to unravel new molecular and cellular mechanisms related to intercellular communication in diabetes. EVs influence pathological phenotypes in several diseases, including diabetes mellitus; however, diabetes has not been shown to alter the size of EVs. Exosomes, which are about ∼100 nanometers in diameter, are a subtype of EVs and originate in endosomes through sequential interplay with other vesicles and cell organelles. Exosomes contain diverse sets of molecules, including nucleic acids, short‐chain peptides, amino acids, lipids, cholesterols, ceramides, and metabolites. Under healthy conditions, exosomes contain constituents that are vital for the homeostasis of neighboring cells; however, under diabetic conditions, these exosomes acquire mesenchymal and fibrogenic molecules, which promote mesenchymal activation through epithelial‐to‐mesenchymal transition, endothelial‐to‐mesenchymal transition, and macrophage‐to‐mesenchymal transition in epithelial cells, endothelial cells, and M2‐type macrophages, respectively. EVs produced by stem cells may be used to treat or arrest diabetic complications. Islets from early‐stage type I diabetic patients could be safeguarded or even restored thanks to the immunomodulatory and reparative characteristics of stem cell‐derived exosomes. In this review, we describe EV constituents in non‐diabetic and diabetic conditions and their effects on mesenchymal activation and fibrogenesis in neighboring cell types, which lead to organ fibrosis. Targeting EVs offers a future therapeutic strategy to better understand diabetes mellitus and its associated fibrogenic complications in cells and tissues. The detection of exosomes in biological fluids offers a potential opportunity to establish them as diagnostic markers of diabetes mellitus.