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This two-sample Mendelian randomization (MR) study was conducted to investigate the causal associations between type 2 diabetes mellitus (T2DM) and the risk of pancreatic cancer (PaCa), as this causal relationship remains inconclusive in existing MR studies. The selection of instrumental variables for T2DM was based on two genome-wide association study (GWAS) meta-analyses from European cohorts. Summary-level data for PaCa were extracted from the FinnGen and UK Biobank databases. Inverse variance weighted (IVW) and four other robust methods were employed in our MR analysis. Various sensitivity analyses and multivariable MR approaches were also performed to enhance the robustness of our findings. In the IVW and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analyses, the odds ratios (ORs) for each 1-unit increase in genetically predicted log odds of T2DM were approximately 1.13 for PaCa. The sensitivity tests and multivariable MR supported the causal link between T2DM and PaCa without pleiotropic effects. Therefore, our analyses suggest a causal relationship between T2DM and PaCa, shedding light on the potential pathophysiological mechanisms of T2DM's impact on PaCa. This finding underscores the importance of T2DM prevention as a strategy to reduce the risk of PaCa., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Evidence on pancreatic cancer (PaCa) risk factors from large population-based cohort studies is limited. This study investigated the PaCa risk factors and the population attributable fraction (PAF) of modifiable risk factors in the UK Biobank cohort. The UK Biobank is a prospective cohort consisting of 502,413 participants with a mean follow-up time of 8.2 years. A binomial generalized linear regression model was used to calculate relative risks for PaCa risk factors. PAF was calculated to estimate the proportional reduction in PaCa if modifiable risk factors were to be eliminated. A total of 728 (0.14%) PaCa incident cases and 412,922 (82.19%) non-PaCa controls were analyzed. The non-modifiable risk factors included age and gender. The modifiable risk factors were cigarette smoking, overweight and obesity, increased waist circumstance, abdominal obesity, Diabetic Mellitus (DM), and pancreatitis history. The PAF suggested that eliminating smoking and obesity can contribute around a 16% reduction in PaCa cases while avoiding abdominal obesity can eliminate PaCa cases by 22%. Preventing pancreatitis and DM could potentially reduce PaCa cases by 1% and 6%, respectively. This study has identified modifiable and non-modifiable PaCa risk factors in the UK population. The PAF of modifiable risk factors can be applied to inform PaCa prevention programs., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.