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Updated: Jun 9, 2025
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Published on: April 19, 2013
High expression of CNOT6L contributes to the negative development of type 2 diabetes
Yuna Zhang1, Guihong Liu1, Haiyan Ding1
1Department of Endocrinology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China.
Objective:
Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by reduced responsiveness of body cells to insulin, leading to elevated blood sugar levels. CNOT6L is involved in glucose metabolism, insulin secretion regulation, pancreatic beta-cell proliferation, and apoptosis. These functions may be closely related to the pathogenesis of T2D. However, the exact molecular mechanisms linking CNOT6L to T2D remain unclear. Therefore, this study aims to elucidate the role of CNOT6L in T2D.
Methods:
The T2D datasets GSE163980 and GSE26168 profiles were downloaded from the Gene Expression Omnibusdatabase generated by GPL20115 and GPL6883.The R package limma was used to screen differentially expressed genes (DEGs). A weighted gene co-expression network analysis was performed. Construction and analysis of the protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis, and comparative toxicogenomics database (CTD) analysis were performed. Target Scan was used to screen miRNAs that regulate central DEGs. The results were verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), and blood glucose measurements in mice.
Results:
A total of 1951 DEGs were identified. GO and KEGG enrichment analysis revealed that differentially expressed genes were mainly enriched in the insulin signaling pathway, ECM-receptor interaction, and PPAR signaling pathway. Metascape analysis indicated enrichment primarily in the cAMP signaling pathway and enzyme-linked receptor protein signaling pathway. WGCNA analysis yielded 50 intersecting genes. PPI network construction and algorithm identification identified two core genes (CNOT6L and GRIN2B), among which CNOT6L gene was associated with multiple miRNAs. CTD analysis revealed associations of core genes with type 2 diabetes, diabetic complications, dyslipidemia, hyperglycemia, and inflammation. WB and RT-qPCR results showed that in different pathways, CNOT6L protein and mRNA levels were upregulated in type 2 diabetes.
Conclusion:
CNOT6L is highly expressed in type 2 diabetes mellitus, and can cause diabetes complications, inflammation and other physiological processes by regulating miRNA, PPAR and other related signaling pathways, with poor prognosis. CNOT6L can be used as a potential therapeutic target for type 2 diabetes.
Insights
CNOT6L is upregulated in type 2 diabetes (T2D) and linked to complications. This gene, involved in key metabolic pathways, represents a potential therapeutic target for T2D management.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
Background:
- Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by insulin resistance and hyperglycemia.
- The specific molecular mechanisms underlying T2D pathogenesis are not fully understood.
- CNOT6L's role in glucose metabolism and insulin regulation suggests a potential link to T2D.
Purpose of the Study:
- To elucidate the precise role and molecular mechanisms of CNOT6L in the pathogenesis of Type 2 Diabetes (T2D).
- To investigate the association between CNOT6L expression and T2D-related physiological processes.
Main Methods:
- Analysis of publicly available T2D datasets (GSE163980, GSE26168).
- Differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network construction.
- Functional enrichment analysis (GO, KEGG, Metascape), miRNA target prediction, and Comparative Toxicogenomics Database (CTD) analysis.
- Validation using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), and in vivo blood glucose measurements.
Main Results:
- 1951 differentially expressed genes (DEGs) were identified, enriched in insulin signaling and PPAR pathways.
- WGCNA and PPI network analysis identified CNOT6L and GRIN2B as core genes, with CNOT6L linked to multiple miRNAs.
- CTD analysis associated core genes with T2D, diabetic complications, dyslipidemia, hyperglycemia, and inflammation.
- CNOT6L mRNA and protein levels were significantly upregulated in T2D, confirmed by RT-qPCR and WB.
Conclusions:
- CNOT6L is highly expressed in Type 2 Diabetes Mellitus (T2DM) and contributes to T2DM complications and inflammation via miRNA and PPAR signaling pathways.
- Elevated CNOT6L expression is associated with a poor prognosis in T2D.
- CNOT6L emerges as a promising potential therapeutic target for managing Type 2 Diabetes.
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