Wnt3a Downregulation Contributes to Type 2 Diabetes Mellitus by Impairing Pancreatic β-Cell Function

To determine the expression and clinical association of Wnt3a in T2DM, and to explore its correlation with β-cell functional parameters. Bioinformatics analysis was performed using the GSE25724 dataset. A case-control study (n = 1026) was conducted to measure serum Wnt3a and genotype Wnt3a rs12401893. High-fat diet (HFD)-induced mice, Wnt3a knockout mice, and AAV-mediated Wnt3a overexpression were used for in vivo experiments. Insulin-resistant MIN6 cells with Wnt3a knockdown or recombinant Wnt3a treatment were used for in vitro assays. Wnt3a was significantly downregulated in pancreatic tissues of T2DM patients. Serum Wnt3a was lower in T2DM patients (AUC = 0.733) and correlated with metabolic parameters. The GG genotype of rs12401893 was associated with higher T2DM risk, while AA+GA was protective. In HFD mice, serum and pancreatic Wnt3a were decreased, accompanied by insulin resistance and islet damage. In vitro, Wnt3a knockdown impaired β-cell function, whereas recombinant Wnt3a improved it. In vivo, Wnt3a deficiency aggravated HFD-induced metabolic disorders, and Wnt3a overexpression alleviated hyperglycemia and preserved islet function. Wnt3a levels are correlated with β-cell functional markers and glucose tolerance in vitro and in vivo. Wnt3a may serve as a potential adjunctive biomarker for T2DM, and its candidacy as a therapeutic target warrants further investigation.