The Impact of lncRNAs in Diabetes Mellitus: A Systematic Review and In Silico Analyses

Abstract

Long non-coding RNAs (lncRNAs) are non-coding transcripts that have emerged as one of the largest and diverse RNA families that regulate gene expression. Accumulating evidence has suggested a number of lncRNAs are involved in diabetes mellitus (DM) pathogenesis. However, results about lncRNA expressions in DM patients are still inconclusive. Thus, we performed a systematic review of the literature on the subject followed by bioinformatics analyses to better understand which lncRNAs are dysregulated in DM and in which pathways they act. Pubmed, Embase, and Gene Expression Omnibus (GEO) repositories were searched to identify studies that investigated lncRNA expression in cases with DM and non-diabetic controls. LncRNAs consistently dysregulated in DM patients were submitted to bioinformatics analysis to retrieve their target genes and identify potentially affected signaling pathways under their regulation. Fifty-three eligible articles were included in this review after the application of the inclusion and exclusion criteria. Six hundred and thirty-eight lncRNAs were differentially expressed between cases and controls in at least one study. Among them, six lncRNAs were consistently dysregulated in patients with DM (Anril, Hotair, Malat1, Miat, Kcnq1ot1, and Meg3) compared to controls. Moreover, these six lncRNAs participate in several metabolism-related pathways, evidencing their importance in DM. This systematic review suggests six lncRNAs are dysregulated in DM, constituting potential biomarkers of this disease.

Serum Long Non-Coding RNAs in Diabetic Kidney Disease

“…The current study did not reveal any association of MALAT1 or CASC2 with the occurrence of T2DM, DKD, or other major micro-or macrovascular diabetic complications. It is obvious that discrepant findings are not uncommon among lncRNA disease association studies [14].…”

“…First, a great deal of these studies were performed in in-vitro models or experimental animals; so their results may not be readily extrapolated to humans. Second, human studies were very divergent regarding the body tissue or fluid studied, the method of lncRNA analysis, the expression of lncRNA level, and even the nomenclature of the lncRNA themselves, making pooled analysis of data difficult [14]. Third, stratification of human studies by the target tissue/fluid results in multiple study groups, each having a relatively low statistical power.…”

“…More importantly, a significant proportion of studies yielded really discordant results. Indeed, among 638 lncRNAs that were differentially expressed between diabetic patients and controls in different studies, only 6 lncRNAs (< 1%) were consistently dysregulated (significantly higher or lower in cases compared with controls in > ¾ of eligible studies) [14]. Although this pooled analysis reported MALAT1 as consistently upregulated in diabetic patients, we found no significant differences in serum MALAT1 expression levels among controls and diabetic patients stratified by UACR; and a recent study found MALAT1 to be even significantly reduced in sera of 60 T2DM patients compared with 60 control subjects [29].…”

“…Therefore, lncRNAs have recently emerged as novel markers for early diagnosis and prognosis of DKD; and might also provide potential therapeutic targets [9]. However, a recent systematic review found that the impact of most lncRNAs studied in DM was inconsistent, due to the absence of standardized nomenclature and quantification techniques, as well as a paucity of studies evaluating a given lncRNA in specific body tissue or fluid [14]. Moreover, most lncRNA studies in the context of DKD were performed on in-vitro models or experimental animals, with relatively few human studies [9].…”

The Cohesin Complex and Its Interplay with Non-Coding RNAs

“…They achieve transcriptional control through interaction with DNA, RNA, and proteins and have the ability to alter chromosomal architecture [ 145 ]. Due to their numerous functional roles, lncRNAs take a major regulatory part in a broad range of hereditary and sporadic diseases including developmental disorder syndromes, diabetes, acute injuries, and cancers [ 3 , 146 , 147 , 148 , 149 ]. For example, the lncRNA mouse maternal expressed gene 3 (MEG3) was shown to play a role in insulin biosynthesis in pancreatic islets.…”