Current Insights into miRNA and lncRNA Dysregulation in Diabetes: Signal Transduction, Clinical Trials and Biomarker Discovery

Abstract

Diabetes is one of the most frequently occurring metabolic disorders, affecting almost one tenth of the global population. Despite advances in antihyperglycemic therapeutics, the management of diabetes is limited due to its complexity and associated comorbidities, including diabetic neuropathy, diabetic nephropathy and diabetic retinopathy. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are involved in the regulation of gene expression as well as various disease pathways in humans. Several ncRNAs are dysregulated in diabetes and are responsible for modulating the expression of various genes that contribute to the ‘symptom complex’ in diabetes. We review various miRNAs and lncRNAs implicated in diabetes and delineate ncRNA biological networks as well as key ncRNA targets in diabetes. Further, we discuss the spatial regulation of ncRNAs and their role(s) as prognostic markers in diabetes. We also shed light on the molecular mechanisms of signal transduction with diabetes-associated ncRNAs and ncRNA-mediated epigenetic events. Lastly, we summarize clinical trials on diabetes-associated ncRNAs and discuss the functional relevance of the dysregulated ncRNA interactome in diabetes. This knowledge will facilitate the identification of putative biomarkers for the therapeutic management of diabetes and its comorbidities. Taken together, the elucidation of the architecture of signature ncRNA regulatory networks in diabetes may enable the identification of novel biomarkers in the discovery pipeline for diabetes, which may lead to better management of this metabolic disorder.

LncRNA NEAT1/miR-146a-5p Axis Restores Normal Angiogenesis in Diabetic Foot Ulcers by Targeting mafG

“…The dysregulation of non-coding RNAs is reportedly involved in the pathogenesis of various diseases, including DFU [ 33 , 34 , 35 ]. Competitive endogenous RNA (ceRNA) binding is a novel hypothesis where the endogenous miRNA shares its miRNA response element (MRE) with lncRNA [ 36 , 37 ].…”

Exploring the theranostic potentials of miRNA and epigenetic networks in autoimmune diseases: A comprehensive review

“…Additionally, T1D is frequently characterized by endothelial homeostasis maintained by miRNA‐126. Additionally, miRNA‐126 regulates endothelial inflammation in individuals with micro/macrovascular problems related to T1D, establishing a connection between these issues and reduced levels of miRNA‐126 43 …”

“…Small endogenous miRNAs are predisposed to control cellular cycles, proliferation, differentiation, and apoptosis by inhibiting the biogenic molecules that control these processes, such as RNA transcripts, or by degrading mRNA 43 . According to various research groups, miRNA‐375 was upregulated, impacting the beta cells that secrete insulin and other miRNA molecules such as miRNA‐29a, miRNA‐29b, miRNA‐200, and miRNA‐7 44 .…”

“…Additionally, miRNA-126 regulates endothelial inflammation in individuals with micro/macrovascular problems related to T1D, establishing a connection between these issues and reduced levels of miRNA-126. 43 The NF-κB response triggered by lipopolysaccharide in monocytes and dendritic cells serves as a phenotypic characteristic and a potential indicator of pathogenic processes in human T1D. 47 In animal murine models of T1D, it has been observed that TNF receptor-associated factor 6 (TRAF6) plays a mediating role in endothelial damage induced by high glucose levels, and this process is governed by signaling pathways involving NF-κB and AP-1.…”

“…42 Small endogenous miRNAs are predisposed to control cellular cycles, proliferation, differentiation, and apoptosis by inhibiting the biogenic molecules that control these processes, such as RNA transcripts, or by degrading mRNA. 43 According to various research groups, miRNA-375 was upregulated, impacting the beta cells that secrete insulin and other miRNA molecules such as miRNA-29a, miRNA-29b, miRNA-200, and miRNA-7. 44 A crosssectional nested, case-control-based research study was carried out by Barutta and colleagues, to look at the differential expression of miRNAs in the blood samples of patients suffering from T1D.…”