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

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.

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.

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.

This study positions PAM as a clinically relevant therapeutic target for T2D, offering new opportunities for β-cell preservation therapies and diagnostic biomarker development.