Insulin Resistance Drives Carcinogenesis by Activating IGF-1 and Oncogenic Pathways

Traditionally viewed within endocrinology, insulin resistance (IR) is increasingly recognized as a broader systemic condition influencing carcinogenesis. Chronic hyperinsulinemia, a hallmark of IR, acts as a mitogenic signal, shifting cellular signaling from metabolic regulation towards growth promotion. This metabolic dysregulation creates a biochemical environment that favors tumor initiation and progression, underscoring a critical gap in understanding cancer etiology beyond genetic mutations.

This comprehensive review systematically analyzed the intricate relationship between insulin resistance (IR) and cancer development. The authors synthesized evidence from numerous preclinical and clinical studies, focusing on the molecular mechanisms by which chronic hyperinsulinemia contributes to carcinogenesis. They explored key signaling pathways, identified potential metabolic biomarkers, and discussed various preventive and therapeutic strategies targeting IR in the context of cancer. The review's scope encompassed cellular proliferation, survival, and metabolic reprogramming influenced by IR.

The review elucidated that chronic hyperinsulinemia, a hallmark of insulin resistance, shifts signaling from metabolic regulation to growth promotion by cross-activating IGF-1 receptors. This engagement triggers critical oncogenic cascades, primarily the PI3K/Akt/mTOR and MAPK pathways, which are central to cellular proliferation, survival, and metabolic reprogramming in cancer cells. Under physiological conditions, insulin primarily signals via InsR for metabolic homeostasis, while IGF-1 predominantly binds to IGF-1R for mitogenic effects. However, in IR, sustained high insulin levels can bind to IGF-1R and hybrid InsR/IGF-1R complexes, amplifying growth-promoting signals. This mechanistic understanding underscores IR's role as a systemic metabolic risk state for various cancers, emphasizing the importance of metabolic dysregulation in oncogenesis.

Elevated insulin levels, beyond their metabolic role, act as a mitogenic signal, directly fostering an environment conducive to tumor initiation and progression.