Diabetes is one of the common chronic metabolic diseases, and its rising incidence year by year not only has a serious impact on people's lives, but also poses a heavy burden on global healthcare. Exosomes have been shown to make promising nanostructures for treating diabetes and are attracting great interest from scientists. Creative Biolabs has many years of research experience in custom preparation and functional validation of exosomes and can provide clients with exosome development services related to the study of diabetes and its complications.

Pathogenesis of Diabetes and Diabetic Foot Ulcers

Diabetes is a disease in which the metabolism of protein, fat and carbohydrates is disturbed, and its common types are type I diabetes mellitus (TIDM) and type II diabetes mellitus (TIIDM). Among them, TIDM is an autoimmune disease in which the immune system impairs the ability of β cells in the pancreas to secrete insulin. Genomic experiments have revealed that most of the genes associated with diabetes are expressed in pancreatic β cells and regulate immune, inflammatory and apoptotic activities in the cells. The difference is that the pathogenesis of TIIDM is a combination of insulin resistance and hypersecretion, which accounts for the majority of diabetic patients. Insulin is essential for the metabolic processes of protein, fat and sugar, maintaining the normal storage of glycogen, fat and protein in the body, avoiding excessive accumulation of blood glucose, ketosis triggered by ketone bodies of lipolysis and loss of functional proteins. Therefore, insulin sensitivity and insulin-secreting β cells are essential to ensure normal metabolism.

Genetic, hypoxic and inflammatory factors also increase the risk of developing diabetes. For example, genetic polymorphisms in OCT3 and GCK have been identified in patients with TIIDM, while Ghrelin and GLP-1-expressed peptide hormones favor improved metabolism. Hypoxia induces endoplasmic reticulum stress and β-cell apoptosis by upregulating the expression of Grp94 and p38. Oxidative stress and inflammatory responses promote the onset of diabetes-mediated atherosclerosis, which involves a variety of genes, including Cyp4a14, P2X7, CTGF and P2Y12.

Diabetic foot ulcers, one of the malignant complications of diabetes, arise from changes in the structure of the foot due to lower limb neuropathy in metabolic disorders of diabetes, accompanied by sensory neuropathy that weakens sensory awareness and eventually unconscious pressure damage to the foot and skin ulceration. The tendency to develop foot ulcers in more than 30% of diabetic patients puts the risk of death within 5 years as high as 80%, so early detection and treatment is necessary to prevent ulcers from deteriorating to the point of requiring amputation. The accumulation of blood glucose due to impaired metabolism interferes with inositol synthesis and nerve conduction, while reduced protein synthesis in diabetes disrupts matrix metalloproteinase-mediated extracellular proteolysis. These negative factors, together with inflammation and hypoxia, impede the process of angiogenesis and wound healing, in which fibroblasts are involved.

Fig.1 A summary of exosomes and their potential in diabetes treatment. (Ashrafizadeh, 2022)

Inherent Properties of Therapeutic Exosomes for Diabetes

A variety of cell-derived exosomes may be used as a non-cellular therapeutic strategy to improve diabetes and foot ulcers because they have similar therapeutic effects to those of their donor cells. For example, brown adipocyte-derived exosomes, which are rich in mitochondria-related components, increased metabolism in mice on a high-fat diet by stimulating cellular oxygen consumption and myocardial function, and accelerated fibroblast proliferation and healing of foot ulcer skin. Another promising donor source is mesenchymal stem cells (MSCs), whose upregulation of metabolism by exosomes involves the activation of LC3-II and Beclin-1-mediated autophagic pathways and the delivery of miRNA-21, which inhibits Grp94 expression. These exosomes can be obtained from cardiomyocytes and hepatic stellate cells. Thus, the function of exosomes as regulators of metabolism has been highlighted by a variety of experimental facts.

Regeneration of β-cells and insulin sensitivity are also important therapeutic aims in diabetes. regeneration of pancreatic β-cells and reduction of blood glucose were significantly detected after injection of MSCs-derived exosomes in an animal model of TIDM. Analysis of PDX-1, TGF-β and Smad2/3 expression revealed that the upregulation of these signals complemented the molecular mechanisms that improve β-cell function. Reduced insulin sensitivity was induced by high intake of fatty acids, such as palmitic acid, which interfered with phosphorylation of insulin receptor substrate 2, inducing apoptosis and insulin resistance in INS-1 cells. Exosomes isolated from umbilical cord mesenchymal stem cells in one experiment stimulated insulin sensitivity in adipocytes by elevating the expression of insulin receptor substrate 1 and deacetylase SIRT1 from the mRNA level, accompanied by a decrease in leptin. miRNA-3075 was detected in hepatocyte-derived exosomes as a key molecule for enhancing insulin sensitivity with the ability to downregulate the fatty acid hydroxylase FA2H, also avoiding the pro-inflammatory effects of fatty acids.

For diabetic foot ulcers, exosomes from various sources such as endothelial progenitor cells and human amniotic epithelial cells, for example, have been found to contain goods such as FGF, VEGF, CXCL-16 and IL-8, which are beneficial in promoting wound healing. In addition, due to the presence of miRNA-146a, MSCs-derived exosomes have been shown to be beneficial in restoring neurotransmission and alleviating neuropathy.

Fig.2 Therapeutic mechanisms of exosomes in diabetes. (Ashrafizadeh, 2022)

Therapeutic Exosomes as Delivery Vehicles

Traditional natural drugs of plant origin, such as curcumin, quercetin and resveratrol, which contain multiple siRNAs and shRNAs in their composition, can provide broad-spectrum treatment of diabetes in a variety of ways, including antioxidant, anti-inflammatory and anti-apoptotic. However, problems such as the degradation of siRNAs in the serum and the low bioavailability of drugs affect the optimal efficacy. Due to the properties of nanostructures such as cargo protection and drug slow release effect, exosome-based delivery vehicles have become a focus of future research. The modifiable potential of surface peptides facilitates the recognition interaction of exosomes with target cells, providing not only a sustained release of drugs to focal cells but also avoiding the possibility of cargo degradation during long circulation. Therefore, the prospect of exosomal delivery of existing drugs or non-coding RNAs of key genes is to be favored.

Improvements and innovations in diabetes treatment strategies are of great interest. Exosomes have been shown to have the potential to regulate metabolism, β-cell function and insulin sensitivity, as well as serve as drug carriers to provide new ideas for the treatment of diabetes. Creative Biolabs has been dedicated to accumulating research experience in the development and functional analysis of exosomes related to a variety of diseases, and is able to provide researchers with high-quality customized exosome services related to diabetes and its complications. services. Please contact us with your interest.

Reference

1. Ashrafizadeh, M.; et al. Exosomes as promising nanostructures in diabetes mellitus: From insulin sensitivity to ameliorating diabetic complications. Int J Nanomedicine. 2022, 17: 1229-1253.

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