Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

Abstract

Diabetes mellitus (DM) is among the chronic metabolic disorders that its incidence rate has shown an increase in developed and wealthy countries due to lifestyle and obesity. The treatment of DM has always been of interest, and significant effort has been made in this field. Exosomes belong to extracellular vesicles with nanosized features (30-150 nm) that are involved in cell-to-cell communication and preserving homeostasis. The function of exosomes is different based on their cargo, and they may contain lipids, proteins, and nucleic acids. The present review focuses on the application of exosomes in the treatment of DM; both glucose and lipid levels are significantly affected by exosomes, and these nanostructures enhance lipid metabolism and decrease its deposition. Furthermore, exosomes promote glucose metabolism and affect the level of glycolytic enzymes and glucose transporters in DM. Type I DM results from the destruction of β cells in the pancreas, and exosomes can be employed to ameliorate apoptosis and endoplasmic reticulum (ER) stress in these cells. The exosomes have dual functions in mediating insulin resistance/sensitivity, and M1 macrophage-derived exosomes inhibit insulin secretion. The exosomes may contain miRNAs, and by transferring among cells, they can regulate various molecular pathways such as AMPK, PI3K/Akt, and β-catenin to affect DM progression. Noteworthy, exosomes are present in different body fluids such as blood circulation, and they can be employed as biomarkers for the diagnosis of diabetic patients. Future studies should focus on engineering exosomes derived from sources such as mesenchymal stem cells to treat DM as a novel strategy.

Keywords: diabetes mellitus; exosome; glucose uptake; insulin resistance; lipid metabolism.

Figure 1

The biogenesis and secretion of exosomes in cells. The biogenesis of exosomes is started from the endocytic pathway. After the formation of early endosomes, they are transformed into multivesicular bodies, followed by two pathways, including ESCRT-dependent and -independent mechanisms, for further processing of exosomes and their secretion. Then exosomes can affect targeted cell based on their cargo that can be proteins, lipids, and nucleic acids.

Figure 2

Exosomes in glucose and lipid metabolism as well as regulating β cell function. The exosomes derived from macrophages may contain miRNA-210 and miRNA-530 and are involved in carbohydrate catabolism. The exosomes can increase levels and activities of GLUT1 and GLUT4 to promote glucose uptake and enhance its metabolism in cells. Furthermore, exosomes can enter into β cells to prevent apoptosis and enhance their viability to maintain their capacity in insulin secretion.

Figure 3

Exosomes and insulin resistance/sensitivity in DM. The exosomes demonstrate dual function in DM and can mediate both insulin resistance and sensitivity. For instance, exosomes derived from M1 macrophages can induce insulin resistance and are rich in PI3K and Ptch; on the other hand, exosomes derived from mesenchymal stem cells and hepatocytes induce insulin sensitivity via affecting molecular pathways such as SIRT1 and Akt as well as transferring miRNAs.

Figure 4

Exosomes and diabetic complications. The various kinds of diabetic complications, including eye disorders, cardiovascular diseases, nephropathy, neuropathy, delayed wound healing, and endothelial dysfunction, can be ameliorated by exosomes. Neuropathy and nephropathy are the most common diabetic complications. Apoptosis, autophagy, angiogenesis, and fibrogenesis are among the most common molecular mechanisms affected by exosomes in alleviating diabetic complications.

Figure 5

A summary of exosomes and their potential in DM treatment. This schematic demonstrates that glucose and lipid metabolism, viability and survival of β cells, and important molecular mechanisms such as apoptosis and ER stress are tightly regulated by exosomes to provide new insight into the treatment of DM and its complications.