Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a high-burden disease worldwide with increasing incidence, poor prognosis, and high mortality. Complete surgical resection is the only potentially curative treatment; however, due to a lack of symptoms in the early stages, most patients have advanced disease when diagnosed. Type 2 diabetes mellitus (T2DM) is a significant health concern characterized by hyperglycemia, insulin resistance, and impairment in insulin secretion. T2DM is linked with PDAC, sharing a complex bidirectional relationship. Therefore, dual causality between the two diseases represents significant challenges in practice, distinguishing existing T2DM as a PDAC risk factor from newly onset, potentially pancreatic cancer-related diabetes (PCRD). Evidence showed that new-onset diabetes (NOD) may serve as a biomarker for early diagnosis of PDAC, and several risk prediction models were developed to identify high-risk patients for further intervention. Although early PDAC detection is important, widespread screening is not currently recommended for T2DM patients due to a lack of cost-effective, efficient screening modalities. However, further risk stratification in diabetic patients is warranted to support a targeted screening strategy with economic viability. Diabetes confers ≈2-fold PDAC risk overall, with the highest relative risk in the first 2-3 years after diagnosis. Strategies using clinical signs (age ≥50-60 years, unintentional weight loss, rapid HbA1c escalation/insulin initiation) and predictive risk scores (e.g., ENDPAC) can triage NOD patients for magnetic resonance imaging/computed tomography (MRI/CT) and endoscopic ultrasound (EUS). A targeted screening approach may allow early diagnosis that could improve the prognosis of PDAC patients. This narrative review aims to synthesize current evidence linking T2DM and PDAC; delineate risk factors within diabetes populations; appraise predictive models and biomarkers for differentiating PCRD from typical T2DM; outline pragmatic, risk-adapted screening strategies, especially for NOD, and identify additional areas where further research is needed.