Elsevier

Clinica Chimica Acta

Volume 497, October 2019, Pages 130-136
Clinica Chimica Acta

Review
The emerging roles of extracellular vesicles in diabetes and diabetic complications

https://doi.org/10.1016/j.cca.2019.07.032Get rights and content

Highlights

  • EV play important roles in the onset and progression of diabetes and diabetic complications, both good and bad.

  • As new players in cell-to-cell communication, EVs have a great potential in the field of drug delivery and disease diagnosis.

  • It is the different miRNAs and proteins inside EVs that endow them with bad or good effects, rather than themselves.

Abstract

Diabetes and diabetic vascular complications are now the leading cause of death in the world. The effects of traditional medical treatment are usually limited and accompanied by many side effects, such as hypoglycemia, obesity, liver and kidney damage, and gastrointestinal adverse reactions. Thus, it is urgent to explore some new strategies for the treatment of patients with diabetes. Recently, extracellular vesicles have received increased attention because of their emerging roles of cell–to–cell communication under physiological and pathological conditions. In addition, because of their abundant existence in almost all body fluids, as well as their plentiful cargos of bioactive proteins and miRNAs they carry, extracellular vesicles have a strong potential for therapeutic and diagnostic applications in many metabolic diseases, such as obesity and insulin resistance. Here, with the aim of providing the basis for the development of new treatments for diabetes, we review current understanding of extracellular vesicles and the critical roles it has played in the onset and progression of diabetes and diabetic complications.

Introduction

The umbrella term extracellular vesicles (EVs) is defined as the lipid bilayer vesicles that carry bioactive proteins, lipids, nucleic acids that interact with and modify target cells [1,2]. Almost all cell types release EVs; thus, they are naturally present in all body fluids, such as blood, urine, saliva, ascites, cerebrospinal fluid, and semen [3]. At present, the extracellular vesicles are proposed to be divided into three parts–exosomes, ectosomes and apoptotic bodies–according to their size and biogenesis [4,5]. Recently, interest in extracellular vesicles has exploded with increasing evidence indicating that EVs play an important role in numerous metabolic diseases, such as obesity, diabetes, and cancer [6,7]. In addition, clinical studies have found that the difference in the number of of EVs and their composition might reflect the pathophysiological conditions of their parent tissue; thus, EVs might serve as potential diagnostic and therapeutic agents in these diseases [[8], [9], [10]]. Since exosomes and ectosomes have many features in common and they are the major causes for inducing metabolic changes in target cells, here, the term "EVs" will be used to refer to these two individual classes of vesicles and their mixture.

First described in the 1980s, exosomes (EXOs) are nanovesicles (30–100 nm in diameter) with bilayer membranes secreted by sheep reticulocytes during differentiation [11]. Exosomes are intraluminal vesicles (ILVs) formed by the inward budding of endosomal membrane to parcel up selective proteins, lipids, and nucleic acids [12]. When endosomes contain a large number of ILVs–also called multivesicular bodies (MVBs)–some of them will fuse with the plasma membrane and secret exosomes extracellularly [13,14].

The terminology of ectosomes is derived from the definition of ectocytosis, introduced in 1991 by Stein and Luzio to depict the vesicles shedding from the plasma membrane of stimulated neutrophils [15]. Ectosomes–also known as microvesicles (MVs), exosome–like vesicles (ELVs) and microparticles (MPs)–are small bilayer membrane vesicles ranging from 100 to 1000 nm in diameter; they can be released by several types of cells, including endotheliocytes, platelets, and monocytes. In contrast with exosomes, ectosomes are formed by outward budding of small plasma membrane domains to wrap special cargos with the assistance of endosomal sorting complex required for transport (ESCRT), and then they are shed from the cell surface [16,17].

Despite differences in their size and generation mechanism, the two classes of EVs have similar functions after releasing (Table 1). Generally, the internalization of EVs by recipient cells occurs mainly through three methods: direct fusion with plasma membranes, ligand–receptor binding, or the endocytic pathway [18]. Once EVs are translated into target cells, such bioactive cargos (mRNA, miRNA, and proteins) as those EVs carried will extensively regulate important metabolic processes, including inflammation and glucose and lipid metabolism. It has been reported, for example, that EVs are released by hepatocytes in response to lipotoxic signals that contribute to local macrophage activation, inflammation and fibrosis [19]. In addition, adipose–derived EVs may modulate insulin–signaling pathways in skeletal muscle and hepatocytes, contributing to obesity associated systemic insulin resistance [20,21]. Thus, given the massive facts that EVs involve in the development of numerous metabolic diseases, as well as the published article which focused on the roles EVs played in the development and treatment of diabetes [22], we will review here the different mechanisms involved in EVs–mediated diabetes and diabetic complications. In doing so, we hope to lay the groundwork for future research and development of EVs in the treatment of diabetes, cancer, obesity, and other metabolic diseases.

Section snippets

EVs in type 1 diabetes

Type 1 diabetes is a T cell–mediated autoimmune disease characterized by the destruction of pancreatic beta cells that lead to insulin deficiency. Type 1 diabetes results from a complicated interaction between genetic and environmental factors. However, the initial trigger for autoimmune processes in type 1 diabetes remains unclear. Lymphocyte infiltration of the islets has been recognized as the onset of type 1 diabetes [24]. Recently, it was found that there are other abnormalities that arise

EVs in type 2 diabetes

Type 2 diabetes results from a progressive defect in insulin production and insensitive response of the body to insulin (also termed insulin resistance, IR). Type 2 diabetes is the most common type of diabetes, and it accounts for 90–95% of all cases of diabetes [31]. Type 2 diabetes is a complex metabolic disorder caused by multiple pathogenic factors, but the mechanisms are not completely understood. Recent studies found that inadequate blood provision to hypertrophic adipose tissue, [32] as

EVs in diabetic vascular complications

Generally, diabetic vascular diseases involve macrovascular (coronary artery disease, peripheral arterial disease, and cerebrovascular disease) and microvascular (nephropathy, retinopathy, and neuropathy) complications [46,47]. Common risk factors for diabetic micro–/macrovascular complications include hyperglycemia, hyperinsulinemia, hypertension, inflammation, dyslipidemia, and blood hypercoagulability [48,49]. Recently, a large number of studies have shown that EVs might contribute to the

Applied prospect of EVs as biological tools for diagnosis and therapy

Today, about 451 million people around the world suffer from diabetes, and the figure is estimated to increase to 693 million by the year 2045 as a result of the worldwide prevalence of obesity [63]. Great expenditures of time and money, as well as resources, both human and material, are put toward preventing and curing diabetes and diabetic complications every year. However, With the gradual deepening studies on EVs, researchers have found some new and promising characteristics of EVs in

Conclusion

In summary, EVs play important roles in the onset and progression of diabetes and diabetic complications. As EVs are natural means of transportation that generate by all kinds of cells, they can be absorbed by their target tissues in a safer and more moderate way than common drug deliveries. It is worth nothing that EVs themselves are not pathogenic for these diseases; it is the different miRNAs and proteins that EVs carry that endow them with bad or good effects. Thus, we should make good use

Funding

This work was supported by National Natural Science Foundation of China (81100106, 81100212, 81670424), Hunan Provincial Natural Science Foundation of China (2018JJ2345), Hunan Provincial Innovation Foundation for Postgraduate (CX2018B617), Scientific Research Foundation for doctor of University of South China (2012XQD37), and the Scientific Research Foundation for the Returned Overseas Scholars of University of South China (2017XQD29).

Declaration of Competing Interest

All authors declare that no conflict of interest exists.

Acknowledgements

The author thanks Lin Chang, research assistant professor, Internal Medicine, Medical School, for valuable discussions and insights on this manuscript. Reviewers are thanked for their suggeations.

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    These authors contributed equally to this work.

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