Extracellular Vesicles in Type 1 Diabetes: A Versatile Tool

Abstract

Type 1 diabetes is a chronic autoimmune disease affecting nearly 35 million people. This disease develops as T-cells continually attack the β-cells of the islets of Langerhans in the pancreas, which leads to β-cell death, and steadily decreasing secretion of insulin. Lowered levels of insulin minimize the uptake of glucose into cells, thus putting the body in a hyperglycemic state. Despite significant progress in the understanding of the pathophysiology of this disease, there is a need for novel developments in the diagnostics and management of type 1 diabetes. Extracellular vesicles (EVs) are lipid-bound nanoparticles that contain diverse content from their cell of origin and can be used as a biomarker for both the onset of diabetes and transplantation rejection. Furthermore, vesicles can be loaded with therapeutic cargo and delivered in conjunction with a transplant to increase cell survival and long-term outcomes. Crucially, several studies have linked EVs and their cargos to the progression of type 1 diabetes. As a result, gaining a better understanding of EVs would help researchers better comprehend the utility of EVs in regulating and understanding type 1 diabetes. EVs are a composition of biologically active components such as nucleic acids, proteins, metabolites, and lipids that can be transported to particular cells/tissues through the blood system. Through their varied content, EVs can serve as a flexible aid in the diagnosis and management of type 1 diabetes. In this review, we provide an overview of existing knowledge about EVs. We also cover the role of EVs in the pathogenesis, detection, and treatment of type 1 diabetes and the function of EVs in pancreas and islet β-cell transplantation.

Keywords: EVs; T1DM; biomarkers; exosomes; extracellular vesicles; islet β-cell transplant; microRNA; pancreas transplant; therapy; type 1 diabetes.

Figure 1

Schematic representation of the biogenesis of EVs: (A) Composition of EVs: EVs consist of cargo made up of bioactive molecules such as proteins, nucleotides, secondary metabolites, and lipids. Heat shock proteins (Hsp90 and Hsp70), Tetraspanins (CD63, CD9, and CD81), cytoskeletal proteins (Fibronectin and Actin), viral proteins (Tsg101), and enzymes are examples of proteins. EVs also contains DNA and RNA. (B) During endosomal maturation, multivesicular bodies (MVBs) develop, and exosomes are released when the MVBs fuse with the plasma membrane. Microvesicles, on the other hand, are derived directly via cell membrane budding and fission. Apoptotic bodies are formed by the death of apoptotic cells.

Figure 2

Processing of glucose in healthy and T1DM patients. (A) As food is ingested in a healthy system, it gets broken down into glucose, which is then released into the bloodstream. In response, the pancreas secretes insulin. Glucose is transported across the membrane via facilitated diffusion. As such, as insulin increases the glucose permeability of cells, this allows the uptake and utilization of glucose. The pancreas is made up of many important cell structures, including the islets of Langerhans. The islets are a low percentage of the total pancreas mass but include cells that are vital in glucose regulation. This includes β-cells, the primary component of islets, making up 65–80% of the total islet cell count. β-cells are responsible for the production and secretion of insulin and amylin. (B) In diabetic patients, as food is digested and converted into glucose to be released into the bloodstream, the normal corresponding insulin response is lacking. This is because the pancreas is no longer producing enough insulin to enable the uptake and utilization of glucose, leading to a state of hyperglycemia. In T1DM, a large number of β-cells in the pancreas are killed due to autoimmune instigated T-cell attacks. Though some β-cells may remain, the pancreas is no longer capable of insulin independence.

Figure 3

Pancreas and islet cell transplantation. (A) In T1DM, many of the islet β-cells die, limiting insulin production and leading to a number of life-long complications. The only near-cure treatment strategy is the transplantation of a pancreas from a healthy donor. In this situation, a pancreas with a small portion of the duodenum attached is inserted into the T1DM patient. With this approach, recipients are able to achieve up to 5 years of insulin independence. (B) Considered an experimental procedure, delivery of islet cells to T1DM patients offers a less invasive and lower risk treatment option, in which islet cells from 1 to 3 healthy donors are isolated and delivered to the pancreas via the portal vein.

Figure 4

EVs in T1DM. EVs can play a valuable role in T1DM. There are a number of RNAs and proteins that are modified in EVs in T1DM and rejected transplants. In addition, the natural components of EVs from a healthy system, such as anti-inflammatory cytokines or micRNAs, can aid in regulating and correcting a disease state. Moreover, EVs can be loaded with particular cargos and delivered alongside transplantation to aid in graft survival and long-term well-being. EVs can be are delivered into the bloodstream where they migrate to distant tissues such as pancreatic islets of Langerhans and are engulfed by target cells. As the EV payload is delivered into a target cell, the proteins and RNA species can have various impacts, triggering diverse cell signaling cascades and the regulation of gene expression.