Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in β cells

Abstract

BACKGROUND Long noncoding RNAs (lncRNAs) and mRNAs are widely involved in various physiological and pathological processes. The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a novel therapeutic strategy that could promote insulin secretion and decrease the rate of β-cell apoptosis in type 2 diabetes mellitus (T2DM) patients. However, the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated. AIM To identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA in β cells, and their roles. METHODS Rat gene microarray was used to screen differentially expressed (DE) lncRNAs and mRNAs in β cells treated with geniposide, a GLP-1RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs. Hub mRNAs were filtered using the STRING database and the Cytoscape plugin, CytoHubba. In order to reveal the regulatory relationship between lncRNAs and hub mRNAs, their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs, and competing endogenous RNA (ceRNA) mechanism was explored through miRanda and TargetScan databases. RESULTS We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of ≥ 1.5 and P value < 0.05. GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway, inflammatory response, calcium signaling pathway, positive regulation of cell proliferation, and ERK1 and ERK2 cascade. Pomc , Htr2a , and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin, CytoHubba. This result was further verified using SwissTargetPrediction tool. Through the co-expression network and competing endogenous (ceRNA) mechanism, we identified seven lncRNAs (NONRATT027738, NONRATT027888, NONRATT030038, etc .) co-expressed with the three hub mRNAs ( Pomc, Htr2a, and Agtr1a ) based on the Pearson coefficient of the expression levels. These lncRNAs regulated hub mRNA functions by competing with six miRNAs ( r no-miR-5132-3p, rno-miR-344g, rno-miR-3075, etc .) via the ceRNA mechanism. Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs, suggesting that it is at a core position within the ceRNA network. CONCLUSION We have identified key lncRNAs and mRNAs, and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA in β cells.

Long Non-Coding RNAs (lncRNAs) in Cardiovascular Disease Complication of Type 2 Diabetes

“…Furthermore, identification of the role of these T2D-lncRNAs may provide a better understanding of the molecular network in the development of T2D. As recently reported, the treatment of glucagon-like peptide-1 receptor agonists (GLP1RAs) in the T2D cell model showed that lncRNA NONRATT027738 is in the core of the molecular networks that resulted in the β-cell improvements following the GLP1ARs treatment [ 93 ].…”

The Beneficial Effects of Geniposide on Glucose and Lipid Metabolism: A Review

“… 43 Geniposide inhibits the early stage of lipotoxicity-induced β-cell apoptosis, and GLP-1R plays a critical role by counteracting lipotoxicity in INS-1 pancreatic islet β cells. 44 Cui et al 45 analyzed the microarray data of INS-1 cells treated with geniposide and identified key lncRNAs and mRNAs in a 2021 study. They found that the lncRNA NONRATT027738 interacts with all three hub mRNAs ( Pomc, Htr2a , and Agtr1a ).…”