Insulin Signaling and Cancer Risk Mechanisms

The insulin signalling cascade, initiated by insulin binding to its tyrosine kinase receptor, orchestrates glucose homeostasis, lipid synthesis and cellular proliferation. Upon receptor activation, insulin receptor substrates recruit phosphoinositide 3-kinase (PI3K), triggering AKT phosphorylation and downstream activation of the mammalian target of rapamycin (mTOR). While this pathway ensures energy storage and growth under normal physiology, chronic perturbations—such as insulin resistance and compensatory hyperinsulinaemia—amplify mitogenic signalling and suppress apoptosis, creating a pro-tumourigenic milieu. Concurrently, elevated insulin enhances the bioavailability of insulin-like growth factors, stimulating their receptors on epithelial and stromal cells to promote proliferation, angiogenesis and invasion. Metabolic reprogramming, characterised by increased glucose uptake, lipid synthesis and reactive oxygen species generation, further drives genomic instability and epigenetic dysregulation. The tumour microenvironment, influenced by adipokines, inflammatory cytokines and altered stromal metabolism in obesity and type 2 diabetes, reinforces malignant phenotypes. Clinically, interventions targeting insulin levels—ranging from lifestyle modification to pharmacological agents such as SGLT2 inhibitors—and disruption of PI3K/AKT/mTOR components represent promising strategies to mitigate insulin-driven cancer risk.

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Insulin Signaling and Cancer Risk Mechanisms publication trend

The graph below shows the total number of articles in insulin signaling and cancer risk mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Hyperinsulinaemia: Excess circulating insulin relative to glucose concentration, often arising from insulin resistance.

Insulin resistance: A state in which target tissues become less responsive to insulin’s metabolic and mitogenic effects.

PI3K/AKT/mTOR pathway: A central intracellular cascade that mediates cell growth, survival and nutrient sensing downstream of insulin receptor activation.

Tumour microenvironment (TME): The local cellular and extracellular milieu surrounding malignant cells, including stromal cells, immune cells and matrix components.

Mendelian randomisation: A method using genetic variants as proxies for modifiable exposures to infer causal relationships in observational data.

Reactive oxygen species (ROS): Highly reactive derivatives of oxygen that can induce DNA damage and promote oncogenic mutations.

References

1. Obesity-induced changes in cancer cells and their microenvironment: Mechanisms and therapeutic perspectives to manage dysregulated lipid metabolism. Seminars in Cancer Biology (2023).
2. Bidirectional Mendelian randomization study of insulin-related traits and risk of ovarian cancer. Frontiers in Endocrinology (2023).
3. Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment. Trends in Cancer (2019).
4. SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia. Cancer & Metabolism (2019).
5. Insulin Resistance and Cancer: In Search for a Causal Link. International Journal of Molecular Sciences (2021).
6. Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer. Epigenetics & Chromatin (2019).
7. Mechanism of the mitogenic influence of hyperinsulinemia. Diabetology & Metabolic Syndrome (2011).
8. Insulin and cancer: a tangled web. Biochemical Journal (2022).
9. The Role for Insulin and Insulin-like Growth Factors in the Increased Risk of Cancer in Diabetes. Rambam Maimonides Medical Journal (2011).