Insulin resistance in cancer risk and prognosis

Obesity-associated insulin resistance (IR) is characterized by a chronic low-grade inflammatory state driven by adipocyte dysfunction, elevated free fatty acids, and proinflammatory cytokines. These factors activate signaling pathways-including JNK, TLR, and NF-κB-that impair insulin receptor function and promote hyperinsulinemia. Elevated insulin reduces insulin-like growth factor binding proteins, thereby increasing the bioavailability of IGF-1 and IGF-2, which stimulate oncogenic pathways such as PI3K-AKT-mTOR and RAS-MAPK. Epidemiological evidence links IR to an increased risk of a broad spectrum of malignancies, though associations vary by cancer subtype, patient demographics, and tumor characteristics. Therapeutic strategies targeting IR-ranging from lifestyle interventions and weight reduction to pharmacological agents like metformin and GLP-1 receptor agonists-have shown promise in reducing cancer risk and improving prognosis. Metformin exhibits anticancer effects through both AMPK-dependent and independent mechanisms, including mTOR inhibition, suppression of cell proliferation, and attenuation of oxidative stress. While observational studies support a relationship between improved insulin sensitivity and reduced cancer risk, definitive evidence from interventional trials remains limited. Overall, these findings underscore the critical role of metabolic dysfunction in tumorigenesis and highlight the potential of IR-targeted therapies in cancer prevention and management.