What Is in the Field for Genetics and Epigenetics of Diabetic Neuropathy: The Role of MicroRNAs

Abstract

Despite the high prevalence of diabetic neuropathy, its early start, and its impact on quality of life and mortality, unresolved clinical issues persist in the field regarding its screening implementation, the understanding of its mechanisms, and the search for valid biomarkers, as well as disease-modifying treatment. Genetics may address these needs by providing genetic biomarkers of susceptibility, giving insights into pathogenesis, and shedding light on how to select possible responders to treatment. After a brief summary of recent studies on the genetics of diabetic neuropathy, the current review focused mainly on microRNAs (miRNAs), including the authors’ results in this field. It summarized the findings of animal and human studies that associate miRNAs with diabetic neuropathy and explored the possible pathogenetic meanings of these associations, in particular regarding miR-128a, miR-155a, and miR-499a, as well as their application for diabetic neuropathy screening. Moreover, from a genetic perspective, it examined new findings of polymorphisms of miRNA genes in diabetic neuropathy. It considered in more depth the pathogenetic implications for diabetic neuropathy of the polymorphism of MIR499A and the related changes in the downstream action of miR-499a, showing how epigenetic and genetic studies may provide insight into pathogenetic mechanisms like mitochondrial dysfunction. Finally, the concept and the data of genotype-phenotype association for polymorphism of miRNA genes were described. In conclusion, although at a very preliminary stage, the findings linking the genetics and epigenetics of miRNAs might contribute to the identification of exploratory risk biomarkers, a comprehensive definition of susceptibility to specific pathogenetic mechanisms, and the development of mechanism-based treatment of diabetic neuropathy, thus addressing the goals of genetic studies.

Peripheral Neuropathy in Diabetes Mellitus: Pathogenetic Mechanisms and Diagnostic Options

“…Genetic research in this field mainly aims to find genetic alterations, variants, or biomarkers associated with an increased risk of developing DPN, to give insights into the pathogenesis, and to find responders to treatment [ 57 ]. Moreover, researchers have paid attention to the possible role of miRNAs, small gene regulators, in the development of diabetes and its micro- and macrovascular complications [ 58 ].…”

“…Moreover, researchers have paid attention to the possible role of miRNAs, small gene regulators, in the development of diabetes and its micro- and macrovascular complications [ 58 ]. For what concerns genes, a role of such as angiotensin converting enzyme (ACE) gene, methylenetetrahydrofolate reductase (MTHFR) gene, glutathione peroxidase-1 (GPx-1) gene, catalase (CAT) gene, and genes associated with the pentose phosphate pathway has been proposed [ 57 ]. Human studies have explored the association between miRNAs and the development of DPN.…”

Multidisciplinary Progress in Obesity Research

“…V. Spallone et al summarized the results of animal and human studies linking microRNAs (miRNAs) to diabetic neuropathy, and explored the possible pathogenic significance of these associations, especially with regard to miR-128a, miR-155a and miR-499a, and their application in the screening of diabetic neuropathy. The authors found that the miRNA gene polymorphism is closely related to diabetic neuropathy [ 104 ]. Axon degeneration is the main pathological feature of many early peripheral neuropathies, including diabetic neuropathy.…”

miRNAs as Biomarkers in Diabetes: Moving towards Precision Medicine

“…miR-155 has been found to have a protective effect in animal studies, by improving insulin sensitivity. The difficulty of further implementing these observations consists of the poor understanding of the time periods in which detection could suggest early subclinical neuropathy [ 90 , 91 ]. Naturally, recent research has shown potential biomarkers for DM that act through their role in mediating inflammation through their axonal regenerative properties.…”

“…However, genetic studies conducted on several polymorphisms of miR146, 128 and 21a genes have concluded that these modifications might have an important role to play within the inflammatory and metabolic pathways that undergo in DN progression. Extensive research must be continued for a better understanding [ 88 , 89 , 91 ].…”