Insulin Resistance: A Systemic Metabolic Risk State Driving Carcinogenesis via Hyperinsulinemia and Inflammation

Traditionally, Insulin Resistance (IR) is primarily associated with type 2 diabetes mellitus (T2DM) and other metabolic disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). However, emerging evidence suggests IR represents a broader systemic metabolic risk state with significant implications for carcinogenesis. The chronic hyperinsulinemia characteristic of IR can activate key pro-growth pathways, while its links to oxidative stress and chronic low-grade inflammation create a tumor-promoting microenvironment. Understanding IR's systemic role is crucial for early cancer risk identification and prevention.

This comprehensive review integrates molecular, epidemiological, biomarker-based, and prevention-oriented perspectives to examine Insulin Resistance (IR) as a systemic metabolic risk state for cancer. Unlike prior reviews focusing on individual mechanisms or epidemiological associations, this work synthesizes diverse data. It emphasizes strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, HOMA-IR, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. The review also considers emerging tools like continuous glucose monitoring and hepatokine profiling to refine risk detection.

The review highlights that chronic hyperinsulinemia, a hallmark of Insulin Resistance (IR), activates insulin-like growth factor-1 (IGF-1) dependent pathways, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling. These pathways collectively promote cellular proliferation and limit apoptosis, fostering a pro-tumorigenic environment. Simultaneously, IR is tightly linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, which together shape a microenvironment conducive to tumor development. Epidemiological studies consistently report associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. The review notes that metabolic dysfunction can occur even in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Causality, however, remains uncertain and likely varies by tumor type. > Integrated biomarker approaches, including HOMA-IR, triglyceride-to-high-density lipoprotein ratio, and IGF-1, are critical for earlier and more accurate IR-associated cancer risk identification.