Multi-Omics Profiling Identifies Biomarker Candidates and Pathogenic Divergence Between Post-Transplant Diabetes Mellitus and Type 2 Diabetes

Abstract Background Post-transplant diabetes mellitus (PTDM) is a significant complication following liver transplantation, primarily induced by immunosuppressive agents like tacrolimus. While PTDM shares some clinical features with type 2 diabetes (T2D), its distinct pathogenesis remains poorly understood. Methods We developed mouse models of PTDM and T2D using tacrolimus, streptozotocin (STZ), and a high-fat diet to simulate disease conditions. Integrated whole-transcriptomics and metabolomics analyses were performed on liver, pancreatic, and adipose tissue to map disease-specific molecular landscapes and nominate candidate biomarkers. Results Despite higher body weight, PTDM mice exhibited lower blood glucose and improved insulin tolerance compared to T2D mice. Multi-omics analyses revealed PTDM-specific activation of the MAPK pathway, marked Treg cell infiltration in in the liver and pancreas, and dysregulation of lincRNA-circRNA networks. Metabolomics identified altered metabolites including 2,2-dimethylsuccinic acid, indicating mitochondrial dysfunction. Most notably, integrative analysis nominated 2510002D24Rik (also known as Pants) — a previously uncharacterized, liver-restricted gene — as a hub coordinating immune-metabolic crosstalk, positioning it as a lead candidate biomarker for PTDM. Conclusions Our multi-omics approach uncovers distinct molecular signatures that differentiate PTDM from T2D, providing novel therapeutic interventions for PTDM.