A multi-omics Mendelian randomization study reveals PAM as a potential therapeutic target for type 2 diabetes.

BACKGROUND: The progression of type 2 diabetes (T2D) is driven by pancreatic β-cell dysfunction and loss, yet current therapies fail to address this core pathophysiology. METHODS: We implemented an integrative pipeline combining genetic and functional data to prioritize T2D targets. We leveraged genome-wide association study (GWAS) and protein quantitative trait loci (pQTL) summary data to infer causal associations between circulating proteins and disease risk. Phenome-wide association studies were conducted to evaluate pleiotropy and potential off-target effects. Single-cell RNA-seq was used to delineate cell-type-specific expression and identify biological pathways associated with candidate genes. Lead candidates were then validated by molecular docking and functional assays. FINDINGS: Mendelian randomization and colocalization analyses prioritized 14 circulating proteins with causal links to T2D, nine of which shared strong causal variants (PPH4 > 0.8). Phenome-wide association studies (PheWAS) excluded off-target effects for 2 candidates (HP and SVEP1). Among the remaining 7 candidates (ENG, GOLM1, GSTA1, HIBCH, PAM, PLXND1, and PTN), PAM (peptidylglycine α-amidating monooxygenase) was found to be expressed in over 80% of β-cells, as revealed by single-cell RNA-sequencing. Moreover, genes co-expressed with PAM were functionally clustered in pathways related to insulin secretion and protein processing. Notably, PAM expression was significantly downregulated in islets of diabetic mice. Molecular docking simulations identified a high-affinity interaction between PAM and oleic acid (OA), a metabolite linked to β-cell function. Strikingly, pharmacological PAM inhibition in INS1 β-cells induced deficits in cell proliferation and survival that were unresponsive to OA supplementation, underscoring PAM's indispensable role in β-cell integrity. INTERPRETATION: This study positions PAM as a clinically relevant therapeutic target for T2D, offering new opportunities for β-cell preservation therapies and diagnostic biomarker development.