Theoretical Considerations Regarding the Role of Hyperinsulinemia and Insulin/IGF Signaling in Cancer Metabolic Reprogramming: Potential Mechanisms and Therapeutic Vulnerabilities

Hyperinsulinemia is increasingly recognized as a systemic factor that can promote tumor progression by amplifying insulin receptor and insulin-like growth factor (IGF) signaling, reshaping cancer-cell metabolism, and influencing the tumor microenvironment. Commonly associated with obesity, type 2 diabetes, and metabolic syndrome, persistent hyperinsulinemia can enhance insulin/IGF receptor signaling and downstream PI3K–AKT–mTOR and RAS–MAPK pathways. These pathways interact with stress-response networks, including NRF2-dependent redox control and AMPK–autophagy signaling, thereby supporting metabolic plasticity under nutrient and microenvironmental stress. Hyperinsulinemia-associated signaling may increase glucose utilization, pentose phosphate pathway activity, glutaminolysis, de novo lipogenesis, and antioxidant capacity, collectively promoting anabolic growth, survival, and treatment adaptation. Metabolic remodeling extends beyond aerobic glycolysis and involves context-dependent alterations in mitochondrial function, oxidative metabolism, lactate production, and metabolic crosstalk among cancer, stromal, and immune cells. Consequently, hyperinsulinemia-associated signaling may contribute to lactate-rich, immunosuppressive tumor microenvironments, tumor progression, and heterogeneous therapeutic responses across cancer types. This review integrates experimental, epidemiological, and translational evidence linking persistent hyperinsulinemia and insulin/IGF signaling with cancer metabolic reprogramming. It critically examines strategies to reduce systemic insulin exposure, inhibit insulin/IGF signaling, or co-target tumor-specific metabolic dependencies, including the metabolic consequences of PI3K-pathway inhibition. By advancing a hyperinsulinemia-centered framework, this review identifies mechanistic gaps and translational priorities for more precise metabolic interventions in cancer.