CTNNB1 Genetic Variation and Its Interaction With DLK1 in Type 2 Diabetes Mellitus

To investigate the association between Catenin Beta 1 (CTNNB1) gene polymorphisms and type 2 diabetes mellitus (T2DM), as well as the interacting molecules of CTNNB1. Bioinformatic analysis of publicly available transcriptomic datasets derived from T2DM samples identified a panel of differentially expressed genes (DEGs), among which CTNNB1 exhibited significant differential expression. Subsequent functional enrichment analysis and molecular docking revealed a co-expression network between CTNNB1 and Delta-like 1 homologue (DLK1). A total of 988 subjects including 455 patients with T2DM and 533 healthy controls were included, and the epidemiological and clinical data were collected. Association between SNPs (rs2953, rs4135387, rs1798802) of CTNNB1 and susceptibility to T2DM was analyzed. CTNNB1 expression was quantified in human serum by ELISA. A mouse model of diabetes was induced by a high-fat diet (HFD). The weight, blood glucose levels, and pancreatic morphology were detected. In a diabetes mouse model, CTNNB1 and DLK1 levels were further assessed using ELISA, Western blot, qRT-PCR, and immunohistochemistry. Immunofluorescence staining was also performed on pancreatic tissue sections to evaluate the spatial relationship within islets between β-catenin and DLK1. Integrated analysis of DEGs and pathway enrichment identified CTNNB1 as a key gene in T2DM. Functional enrichment and molecular docking suggested that CTNNB1 and DLK1 may interact through hydrogen bonding. The CTNNB1 gene rs1798802 locus was associated with T2DM. The proportion of T2DM patients was lower in the GG genotype group than in controls (47.7% vs. 52.3%). The GG genotype of the CTNNB1 gene at the rs1798802 tended to protect the individuals from T2DM (OR = 0.640, 95% CI: 0.446-0.918, p = 0.015). Serum levels of CTNNB1 were significantly reduced in patients with T2DM (74.5 pg/mL vs. 23.78 pg/mL). Compared with control mice, HFD-induced T2DM mice showed significantly decreased protein content and gene expression of β-catenin in the pancreatic tissue, while a concurrent decrease was also observed in DLK1 expression. Immunofluorescence staining revealed a significant overlap in the subcellular distribution of CTNNB1 and DLK1, which supported their potential physical interaction within pancreatic islet cells. The CTNNB1 gene exhibits differential expression in T2DM, and its genetic polymorphisms are also associated with the disease. The CTNNB1 gene rs1798802 loci GG genotype may be a protective factor against T2DM. CTNNB1 may interact with DLK1, potentially contributing to the regulation of pancreatic islet function. The Wnt/β-catenin signaling pathway is inhibited in pancreatic islets in T2DM. β-catenin (CTNNB1) is a potential target for the treatment of T2DM.