The Bidirectional Relationship Between Diabetes and Cancer: Mechanistic Insights, Epigenetic Intermediaries, and Therapeutic Approaches

OBJECTIVES: The global rise in diabetes mellitus parallels an increasing cancer burden, highlighting an incompletely understood relationship between these two complex diseases. Accumulating epidemiological evidence indicates that diabetes is associated with an increased incidence and mortality of several site-specific cancers, whereas cancer and its treatment may contribute to dysglycemia and diabetes through diverse mechanisms. In addition, shared metabolic and environmental risk factors further contribute to the observed association between these conditions. METHODOLOGY: This narrative review comprehensively examined peer-reviewed literature retrieved from PubMed, Scopus, Web of Science, and Google Scholar, focusing on the epidemiological, mechanistic, and epigenetic links between diabetes and cancer. RESULTS: Beyond shared lifestyle risk factors, converging molecular mechanisms-including chronic hyperglycemia, insulin resistance, low-grade inflammation, oxidative stress, and metabolic reprogramming-provide a biological framework linking diabetes and cancer. Emerging evidence suggests that epigenetic dysregulation acts as a central intermediary in this relationship by integrating metabolic stress with sustained alterations in gene expression through DNA methylation, histone modifications, non-coding RNAs, chromatin remodeling, and epigenetic aging. Diabetes-related epigenetic memory, microbiome-driven epigenetic modulation, and sex-specific epigenetic signatures may further contribute to cancer susceptibility and disease heterogeneity, although the strength of evidence varies across experimental and clinical studies. CONCLUSIONS: This review synthesizes current epidemiological, mechanistic, and epigenetic evidence linking diabetes and cancer, with particular emphasis on metabolic-epigenetic crosstalk and clinically relevant signaling pathways. It also critically evaluates the dual metabolic and oncologic effects of antidiabetic and anticancer therapies while highlighting current evidence gaps and the need for precision medicine approaches in the prevention and management of both diseases.