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

β-cells and suggests that abnormal expression of β-cell- Yin et al. (2015) found that downregulating the lncRNA
specific lncRNAs contributes to diabetes pathogenesis. taurine-upregulated gene (TUG1) increased cell death and
Furthermore, HI-LNC45 expression was remarkably reduced insulin secretion from islets both in vitro and
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reduced, whereas KCNQ1 overlapping transcript-1 in vivo. In Min-6 cells, knocking down TUG1 in mice led
concentrations were significantly elevated in the islets to decreased mRNA levels of transcription factors essential
of T2DM patients. Further analysis of 55 T2DM for insulin production and secretion, including glucose
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susceptibility loci revealed that nine contained islet transporter 2 (GLUT2), (MafA), neurogenic differentiation
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lncRNAs within 150 kb of the lead single nucleotide 1 (NeuroD1), Pdx1, and NeuroD2. During pregnancy,
polymorphism, and six of these loci were directly linked Meg3 was identified as a novel lncRNA involved in insulin
to cellular dysfunction. Notably, islet lncRNAHI-LNC25 production and secretion, and its knockdown decreased
was found to potentially regulate GLIS family zinc insulin levels by suppressing key transcription factors such
finger protein 3 (GLIS3), closely associated with T2DM as Pdx1 and MafA. Many lncRNAs likely target similar
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incidence. 15,19-21 These findings highlight islet lncRNAs pathways to regulate insulin secretion. In summary, the
as potential biomarkers for diabetes. Their proximity to data suggest that lncRNAs have therapeutic potential in
islet-specific open chromatin regulatory clusters (COREs) enhancing insulin sensitivity and secretion.
implies possible coregulatory mechanisms with nearby Hepatic insulin resistance is a hallmark of T2DM, as the
protein-coding genes. For example, Fadista et al. (2014) liver plays a critical role in glucose and lipid metabolism.
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demonstrated that paired box 6 (PAX6), synaptotagmin 11 Insulin-stimulated Akt activation primarily inhibits
(SYT11), and the MAP kinase-associated death domain glucose synthesis while promoting glycogen synthesis in
control proinsulin production, insulin exocytosis, and hepatocytes. Several ncRNAs, especially miRNAs, have
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the formation of pancreatic islets in vitro. These genes been found to influence hepatic insulin signaling and
were substantially co-expressed with the islet lncRNA contribute to the development of diabetes.
LOC283177. In light of these findings, further in-depth
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research on the functional role of lncRNAs in regulating 4. Role of lncRNAs in DM complications
diabetes diagnosis and pathogenesis is essential.
Many diabetic complications are linked to microvascular
3. LncRNAs in the regulation of insulin and macrovascular dysfunctions, contributing to
secretion and sensitivity conditions such as retinopathy, nephropathy, and
cardiovascular and peripheral vascular diseases. Several
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Pancreatic β-cells respond to circulating nutrients, of these complications have been associated with specific
enabling the body to release insulin as needed. Diabetes genes (Table 1). These vascular problems often feature
primarily results from either absolute or relative insulin impaired angiogenesis. 29,30 Various lncRNAs associated
insufficiency. Consequently, modern diabetes treatments with diabetes have been shown to regulate angiogenesis
often focus on enhancing insulin sensitivity or secretion. individually, though only a limited number are directly
Various lncRNAs play a role in regulating insulin secretion connected to diabetic vascular complications. In vivo
and sensitivity. For instance, steroid receptor RNA activator vascular development was inhibited by pharmacological
(SRA) has been found to enhance insulin sensitivity and siRNA-induced silencing of metastasis-associated lung
and promote glucose uptake by adipocytes in response adenocarcinoma transcript 1 (MALAT1). In addition,
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to insulin stimulation. The capacity of SRA to control lncRNAs enriched in vascular cells, smooth muscle,
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the expression of multiple components affecting insulin and endothelial cells were initially identified in vascular
sensitivity appears to play a key role in the underlying smooth muscle cells (VSMCs) of coronary arteries.
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mechanisms. For instance, suppression of tumorigenicity Further research found that lncRNAs help maintain
2 in adipocytes overexpressing SRA-like receptors led to a the stability of the contractile phenotype of VSMCs and
reduction in the expression of negative regulators of insulin inhibit VSMC migration. Because VSMC development
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sensitivity. Contrary to negative regulators, such as SH3 in response to hyperglycemia is a hallmark of diabetic
domain-containing 1, suppressors of cytokine signaling -1 cardiovascular complications, researchers identified that
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and 3 promote the expression of positive regulators. lincRNA-p21 suppresses macrophage and VSMC growth
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Researchers have also shown that SRA enhances insulin while inducing cell death through p53 signaling. This
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function, particularly glucose uptake, through the Akt suggests that lincRNA-p21 contributes to diabetic vascular
and forkhead box O1 (FOXO1) signaling pathways. complications or related inflammation. Beyond MALAT1,
Knockdown of SRA using a lentiviral system resulted in which regulates inflammatory cytokine production and
the inhibition of insulin-stimulated glucose uptake and stimulates SAA3 in endothelial cells, no additional
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insulin-stimulated FOXO1 and Akt phosphorylation. 24 experimental data on lncRNAs in diabetic vascular

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