Purpose <p>Pancreatic beta-cell dysfunction is a central pathological feature of type 2 diabetes (T2D). However the cell type-specific causal genes underlying β-cell dysfunction remain incompletely defined.</p> Methods <p>We analyzed scRNA-seq data from 17 patients with T2D and 17 healthy controls. Four machine learning models (Random Forest, XGBoost, SVM, L2 regularized logistic regression) were applied to identify key pathogenic cell types. Differentially expressed genes(DEGs) in beta cells were identified using Seurat, and cis-eQTLs (GTEx v8) were intergrated with T2D summary statistics(FinnGen R12) through Mendelian randomizaition(MR) to identify pancreatic genes causally linked to T2D. Beta-cell-specific causal genes were defined by the intersection of beta-cell DEGs and MR-identified genes. Robustness was assessed by Steiger filtering, Bayesian colocalization (PPH4 &gt; 0.8), and phenome-wide association studies (PheWAS). As additional support, we examined POLK expression in a high-glucose-treated beta-cell line and KCNK17 expression in an independent RNA-seq dataset of palmitate-exposed human islets. Functional enrichment (GO/KEGG) analysis were performed to explore fuctional mechanisms.</p> Results <p>Beta-cells were consistently prioritized as the top contributor to T2D pathogenesis. Integration of scRNA-seq and MR identified eight beta-cell-specificc causal genes. Higher expression of POLK, HLA-C, LINC01099, AGA, and LSAMP increased T2D risk, whereas higher KCNK17 expression was protective, with MR and colocalization results remaining robust across sensitivity analyses. In line with the genetic and single-cell findings, POLK expression was increased in high-glucose-treated beta cells, while KCNK17 expression was reduced in palmitate-exposed human islets. In scRNA-seq defined beta-cell subpopulations, KCNK17⁺ beta-cells were enriched in ion transport and T2D pathways, with POLK⁺ beta-cells showed activation of stress response and pancreatic dysfunction pathways.</p> Conclusions <p>This study identifies KCNK17 and POLK as β -cell-specific genes with potential relevance to T2D pathogenesis and highlights distinct cellular programs associated with ion transport and stress responses. Our findings provide a cell Type-resolved, multi-omics framework for elucidating causal mechanisms underlying β-cell dysfunction in T2D.</p>