Exosomes and Their Noncoding RNA Cargo Are Emerging as New Modulators for Diabetes Mellitus

Abstract

Diabetes belongs to a group of metabolic disorders characterized by long term high blood glucose levels due to either inadequate production of insulin (Type 1 diabetes, T1DM) or poor response of the recipient cell to insulin (Type 2 diabetes, T2DM). Organ dysfunctions are the main causes of morbidity and mortality due to high glucose levels. Understanding the mechanisms of organ crosstalk may help us improve our basic knowledge and find novel strategies to better treat the disease. Exosomes are part of a newly emerged research area and have attracted a great deal of attention for their capacity to regulate communications between cells. In conditions of diabetes, exosomes play important roles in the pathological processes in both T1DM and T2DM, such as connecting the immune cell response to pancreatic tissue injury, as well as adipocyte stimulation to insulin resistance of skeletal muscle or liver. Furthermore, in recent years, nucleic acids containing exosomes-especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)-have been shown to mainly regulate communications between organs in pathological processes of diabetes, including influencing metabolic signals and insulin signals in target tissues, affecting cell viability, and modulating inflammatory pancreatic cells. Moreover, exosome miRNAs show promise in their use as biomarkers or in treatments for diabetes and diabetic complications. Thus, this paper summarizes the recent work on exosomes related to diabetes as well as the roles of exosomal miRNAs and lncRNAs in diabetic pathology and diagnosis in order to help us better understand the exact roles of exosomes in diabetes development.

Keywords: exosomes; long noncoding RNA; miRNA; type 1 diabetes; type 2 diabetes.

Figure 1

Exosome biogenesis and regulation. Schematic representation of exosome biogenesis and uptake. Exosomes are initially formed as intraluminal vesicles by multivesicular bodies (MVBs). MVB formation has two mechanisms. The endosomal sorting complex required for transport (ESCRT)-dependent pathway requires a complex constituent of ESCRT, Vps4 (vacuolar protein sorting-associated protein), and Hsp70 (heat-shock protein). The typical proteins Tsg101 and Alix for exosome identification belong to the ESCRT complex and represent ESCRT. The other pathway involves ESCRT-independent pathways, which are dependent on Hsp70 binding phospholipids to assemble MVBs. After secretion, the recipient cells mainly uptake those exosomes in three ways: (1) endocytosis, by which exosomes enter into the recipient cell cytosol directly; (2) fusion, by which the exosome cargo is mainly released to the recipient cytosol; or (3) ligands, by which exosomes interact with the recipient cells either by inducing internalization or eliciting intracellular signaling cascades without being internalized.

Figure 2

Exosomes regulate diabetic pathological process. Schematic representation of exosomes participating in the pathologies of type 1 diabetes (T1D) and type 2 diabetes (T2D). (a) Immune cell-derived exosomes can activate immune cells and induce β-cell apoptosis and cell death. (b) In certain models, pancreatic islets also release intracellular β-cell autoantigens in exosomes in turn to favor the immune response. (c) Adipocyte-derived exosomes carrying sonic hedgehog (SHH), a protein known to modulate immunity, induce proinflammatory or M1 polarization of bone marrow-derived macrophages and induce insulin resistance in the main insulin-sensitive organs (skeletal muscle, liver, adipose).

Figure 3

The molecular mechanisms by which exosomes containing miRNA and long noncoding RNA (lncRNA) regulate communication between organs. In the diabetic state, miRNA- and lncRNA-carrying exosomes exert their biological function by targeting different tissues. (1) Exosome lncRNA-p3134 was downregulated in a diabetic model, and lncRNA-p3134 could positively regulate glucose-stimulated insulin secretion by promoting key regulators (Pdx-1, MafA, GLUT2, and Tcf7l2) in β-cells. In this case, downregulation of lncRNA-p3134 contributed to the pathology of diabetes. (2) Exosomal miRNA (miR-20b-5p, miR-155, miR-450b-3p, miR151-3p, and miR-29b-3p) was upregulated in the diabetic model and targeted skeletal muscles via various insulin signaling regulatory proteins (PPAR, AKT, GLUT4, and FOXO) and then contributed to the pathology of diabetes. (3) Exosomal miRNA (miR-122, miR-192, miR-27a/b, miR-155, miR-29b-3p) was upregulated in diabetic models and targeted adipocytes via PPAR proteins and then contributed to the pathology of diabetes. (4) Exosomal miRNA (miR-142-3p and miR-142-5p) was upregulated in diabetic models and targeted pancreatic cells via upregulated cytokines, which then contributed to the pathology of diabetes. (5) Other exosomal miRNAs (miR-106, miR-146a, miR-222, and miR-486) are promising therapeutic agents to protect pancreatic cells or treat diabetic complications by targeting certain organs, such as astrocytes, retinal tissue, and renal cells.