Bidirectional relationship between diabetes and pancreatic cancer: from mechanistic investigation to clinical application

A well-established bidirectional causal relationship connects type 2 diabetes mellitus (T2DM) and pancreatic ductal adenocarcinoma (PDAC). Long-standing T2DM elevates pancreatic cancer risk approximately 1.8–2.2-fold, whereas 30%–74% of PDAC patients develop new-onset diabetes (NOD) 2–36 months before tumor detection, which mostly corresponds to tumour-originated type 3c pancreatogenic diabetes (T3cDM). Notably, 25%–40% of such patients achieve spontaneous glycemic recovery after R0 curative resection, solidifying the causal nature of PDAC-induced hyperglycemia. Six interrelated molecular mechanisms mediate their reciprocal crosstalk: chronic metabolic abnormality mediated by hyperinsulinemia and AGE-RAGE signaling, sustained inflammatory and macrophage remodeling, KRAS-driven oncogenic and epigenetic modification, pancreatic stellate cell-derived desmoplasia, tumor exosome-mediated β-cell damage, and gut-pancreas microbiome dysbiosis. Specifically, PDAC-secreted exosomes loaded with adrenomedullin, peritumor fibrotic islet destruction and circulating S100A8 peptide collectively lead to insulin deficiency, making T3cDM biochemically distinguishable from insulin-resistant classic T2DM by reduced pancreatic polypeptide and endogenous insulin concentrations. Clinically, END-PAC scoring and emerging machine learning algorithms facilitate risk stratification for early PDAC screening among patients aged 50 years or older with NOD. Nonetheless, prominent challenges remain: conflicting clinical data on the anti-PDAC potential of metformin and GLP-1RAs, ethnic heterogeneity limiting the generalizability of current prediction models, and up to 88% T3cDM misdiagnosis owing to the absence of global unified diagnostic benchmarks. Future translational research will center on prospective validation of multi-omic biomarkers, formulation of standardized T3cDM diagnostic criteria, large-scale screening trials, and rational repurposing of antidiabetic agents for pancreatic cancer prevention and adjuvant therapy.