Page 22 - GPD-4-2

Gene & Protein in Disease lncRNAs dysregulation in diabetes and its complications

1. Introduction β-cell death, glucose metabolism, and insulin resistance. 9-11
Consequently, various studies have reported changes in the
Noncoding RNAs (ncRNAs) exceeding 500 nucleotides, expression of lncRNAs related to type 1 DM (T1DM) and
known as long ncRNAs (lncRNAs), represent a distinct type 2 DM (T2DM) in murine models. In this context,
11
type of RNA transcript, transcribed from DNA but not lncRNAs may serve as valuable biomarkers for the early
translated into proteins. Numerous recent studies have detection of, and susceptibility to, T1DM or T2DM. 11,12
confirmed that lncRNAs play crucial regulatory roles in For example, Carter et al. (2015) found that growth-arrest-
nearly all biochemical processes and pathways. ncRNAs specific transcript 5 (GAS5) may be a predictive biomarker
1
are classified by length into three main categories: small for T2DM, as this lncRNA was reduced in the serum of
RNAs, which are fewer than 50 nucleotides long; RNA DM patients within a cohort of USA military veterans.
13
polymerase III transcripts, ranging from approximately 50 Individuals with reduced GAS5 expression were nearly
to 500 nucleotides; and lncRNAs, which are typically over 12 times more likely to have T2DM. 14
200 nucleotides. LncRNAs are further categorized by their
origin and characteristics. They may be intergenic, antisense, Current research lacks comprehensive insights into how
intronic, or derived from pseudogenes. Some lncRNAs specific lncRNAs contribute directly to diabetes-associated
resemble messenger RNAs (mRNAs), being spliced and complications. Our review bridges this gap by identifying
polyadenylated, whereas others lack polyadenylation or a various lncRNAs that regulate angiogenesis and vascular
7-methylguanosine cap. In addition, circular RNAs formed cell stability, offering new directions for investigating their
by backsplicing and trans-acting regulatory RNAs are roles in diabetes-induced complications. Furthermore,
classified as lncRNAs. In transcription, posttranscriptional validating specific lncRNAs as reliable biomarkers for
2
regulation, and epigenetics, lncRNAs influence gene DM and its complications is crucial, highlighting their
expression. Current research shows that neurological, potential as noninvasive diagnostic tools and therapeutic
endocrine, and metabolic disorders are closely linked targets. This gap also underscores the need for improved
with lncRNAs. Although mRNAs are expressed at higher delivery methods and robust clinical trials to address
3
levels than most lncRNAs, many lncRNAs play key roles in challenges in translating these findings into effective
4
regulating cellular homeostasis and gene expression. Due clinical applications. Here, we examine the biological
to their abnormal activities in controlling certain biological processes involving lncRNAs in DM, their significant roles
in DM, and summarize the history and general functions
processes and their dysregulated expression in various of lncRNAs. In addition, we explore how lncRNAs can
diseases, lncRNAs have drawn significant attention. Studies function as biomarkers for early diagnosis, prevention, and
indicate substantial variation in the number of noncoding treatment of DM.
genes between species, suggesting that this variation is
related to organismal complexity. Understanding how 2. LncRNAs in pancreatic β-cells
4,5
lncRNAs regulate transcriptional or posttranscriptional
processes, as shown in Figure 1, enhances our knowledge Pancreatic β-cells primarily produce and secrete insulin, a
of disease. hormone that promotes glucose uptake by cells to regulate
blood glucose levels. Exonic readings from proinsulin
Diabetes mellitus (DM) is the most common metabolic mRNA in pancreatic islets were observed 20% of the time,
condition, categorized by a lack of insulin release, impaired whereas this percentage rose to 45% in β-cells, according
insulin action, or both. The global prevalence of DM to a transcriptome study. In recent years, islet lncRNAs
6
15
presents a significant public health challenge due to the have emerged as key regulators of insulin synthesis and
substantial financial burden it places on both patients and release, although it has long been known that several islet-
society. A thorough understanding of DM pathophysiology enriched transcription factors tightly control insulin gene
is crucial for developing more effective preventive and expression. The imprinted noncoding gene known as the
therapeutic strategies. Routine evaluation, early diagnosis, maternally expressed gene (Meg3) is located on mouse
and efficient management of chronic complications are chromosome 12, with its human homolog on chromosome
vital for reducing the morbidity and mortality associated 14. Although Meg3 shows higher expression in normal
with DM. Advances in modern technologies have tissues, it is downregulated in many human cancers or
7,8
identified numerous lncRNAs as novel regulators in tumor-derived cell lines. Meg3 expression within the islet
14
the pathophysiology of DM, potentially offering new of Langerhans is 20 times higher in human β-cells than in
approaches for treatment, early diagnosis, and prevention. α-cells, which produce glucagon, suggesting a specific role
Clinical phenotypes have revealed several correlations in β-cells. Glucose regulates Meg3 expression dynamically,
between altered gene expression and lncRNA physiology. and blocking it with small interfering RNAs (siRNAs) in
LncRNAs play key roles in regulating insulin production, murine insulinoma cell line 6 (MIN6) mouse β-cells leads

Volume 4 Issue 2 (2025) 2 doi: 10.36922/gpd.4000