Diabetes mellitus and ovarian cancer: Intersecting pathways and clinical outcomes

Table 1 Key molecular pathways and mediators through which diabetes mellitus and its metabolic features promote ovarian cancer development and progression

Mechanism	Key mediators	Proposed pro-tumorigenic effects in ovarian cancer
Hyperinsulinemia	Insulin, infrared-A isoform	Activates PI3K/AKT/mTOR and Ras-mitogen-activated protein kinase pathways, promoting cell proliferation and inhibiting apoptosis
IGF-1 axis activation	IGF-1, IGF-1R	Similar to insulin, stimulates growth and survival pathways. Hyperinsulinemia reduces IGFBPs, increasing bioavailable IGF-1
Chronic hyperglycemia	AGEs, reactive oxygen species	Induces oxidative stress, DNA damage, genomic instability, and chronic inflammation, shaping a pro-tumor microenvironment
Hormonal imbalance	Androgens, estrogens	Hyperinsulinemia may increase ovarian androgen production; altered estrogen metabolism may provide additional growth signals
Chronic inflammation	Adipokines, cytokines	Expanded adipose tissue secretes pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6), promoting tumor growth and progression

PI3K/AKT/mTOR: Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin; IGF-1: Insulin-like growth factor-1; IGF-1R: Insulin-like growth factor-1 receptor; IGFBP: Insulin-like growth factor binding proteins; AGE: Advanced glycation end-product.