Abstract
BACKGROUND: Type 2 diabetes mellitus (T2DM) and cancer are both major global public health concerns; however, their causal relationship remains unclear. This study aims to quantitatively investigate the potential causal associations between T2DM and 17 site-specific cancers through a systematic review and meta-analysis of Mendelian randomization (MR) studies. METHODS: We systematically searched Scopus, PubMed, the Cochrane Library, Web of Science, Embase, and Ovid MEDLINE to identify MR studies investigating the association between T2DM and cancer published up to June 2025. A meta-analysis was performed on extracted data, accompanied by heterogeneity testing, sensitivity analysis, and publication bias assessment. RESULTS: The initial search yielded 1,143 articles. After multi-level screening, 44 articles were ultimately included, with 42 articles (comprising 131 MR studies) eligible for meta-analysis. The pooled results demonstrated that T2DM was significantly associated with an increased risk of pancreatic cancer (OR = 1.09, 95% CI: 1.04-1.15, P = 0.0007) and endometrial cancer (OR = 1.07, 95% CI: 1.04-1.09, P < 0.00001). Conversely, T2DM was significantly associated with a decreased risk of gastric cancer (OR = 0.90, 95% CI: 0.85-0.93, P < 0.00001), melanoma (OR = 0.97, 95% CI: 0.95-0.99, P = 0.009), and esophageal cancer (OR = 0.86, 95% CI: 0.79-0.93, P = 0.0002). The effect sizes for T2DM's associations with thyroid and breast cancers were modest, with no clinical significance. No significant causal association was identified between T2DM and the remaining ten cancer types. CONCLUSION: The causal relationship between T2DM and cancer appears to be tissue-specific. T2DM significantly increases the risk of pancreatic and endometrial cancers while demonstrating a negative association with gastric cancer, melanoma, and esophageal cancer. CLINICAL TRIAL REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251066404.