Abstract
The complex bidirectional relationship between diabetes mellitus (DM) and oral cancer (OC) denotes that metabolic dysfunction and malignancy intersect at molecular, cellular, and systemic levels. This state-of-the-art review analyzes the most recent literature data on the multiple interconnected pathways linking DM and OC, including hyperinsulinemia/IGF-1 signaling, chronic hyperglycemia-induced cellular damage, persistent inflammation, immune dysfunction, and oral microbiota dysbiosis. These mechanisms create a permissive environment for oral carcinogenesis while simultaneously impairing the body's natural tumor surveillance systems. Key molecular networks explored include the PI3K/AKT/mTOR pathway, AGE-RAGE interactions, NF-κB signaling, the p53 tumor suppressor pathway, and HIF-mediated responses. Clinical evidence demonstrates that patients with diabetes have higher OC prevalence (250 per 100,000 patients) and significantly increased mortality (HR of 2.09) compared to non-diabetics. The review highlights metformin as the most promising anti-diabetic agent for OC management, showing anti-tumor effects through mTOR inhibition. Novel therapeutics, such as GLP-1 agonists, particularly semaglutide, may be helpful but require further clinical validation. Understanding the shared molecular pathways enables the development of integrated therapeutic strategies that target both conditions simultaneously, and it supports effective screening programs, personalized prevention strategies, and optimized multidisciplinary management approaches for this high-risk patient population.