Gene Dysregulation and Islet Changes in PDAC-Associated Type 3c Diabetes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, often associated with new-onset diabetes. The relationship between PDAC and diabetes, particularly type 3c diabetes, remains poorly understood. This study investigates whether PDAC-associated diabetes represents a distinct subtype by integrating transcriptomic and histological analyses. Whole-tumour RNA sequencing data from The Cancer Genome Atlas (TCGA) were analysed to compare gene expression profiles between PDAC patients with and without diabetes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) deconvolution was employed to assess immune cell populations. Histopathological evaluations of pancreatic tissues were conducted to assess fibrosis and islet morphology. Histological analysis revealed perivascular fibrosis and islet basement membrane thickening in both PDAC cohorts. Transcriptomic data indicated significant downregulation of islet hormone genes insulin (INS) and glucagon (GCG) but not somatostatin (SST) in PDAC-associated diabetes, consistent with a type 3c diabetes phenotype. Contrary to previous reports, no distinct immunogenic signature was identified in PDAC with diabetes, as key immune checkpoint genes (Programmed Cell Death Protein 1 (PDCD1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), Programmed Death-Ligand 1(PD-L1)) were not differentially expressed. The findings suggest that PDAC-associated diabetes arises through neoplastic alterations in islet physiology rather than immune-mediated mechanisms. The observed reductions in endocrine markers reinforce the concept of PDAC-driven β-cell dysfunction as a potential early indicator of malignancy. Given the poor response of PDAC to PD-L1 checkpoint inhibitors, further research is needed to elucidate alternative therapeutic strategies targeting tumour-islet interactions.