Molecular & cellular mechanisms
Insulin resistance arises from a complex interplay of adipose tissue dysfunction, chronic low‑grade inflammation, and impaired insulin signalling.
Central role of visceral adipose tissue (VAT)
- Excess free fatty acids (FFA) from VAT overload muscle and liver, promoting intracellular lipid accumulation (diacylglycerol, ceramides) that interfere with insulin signalling.
- Pro‑inflammatory adipokines (TNF‑α, IL‑6) are elevated, while protective adiponectin is reduced.
- This leads to serine phosphorylation of IRS‑1, blunting the PI3K/Akt pathway and reducing GLUT4 translocation.
Endothelial dysfunction & vascular impact
- Reduced nitric oxide (NO) bioavailability and increased endothelin‑1 contribute to hypertension and microvascular damage.
- Microalbuminuria and elevated CRP are common clinical correlates.
Hormonal drivers in women
- Estrogen decline (menopause) removes a protective effect on insulin sensitivity, shifting fat storage to the abdomen.
- In PCOS, hyperinsulinaemia drives ovarian androgen excess, creating a vicious cycle of IR and metabolic disturbance.
Key molecular targets
- Insulin receptor, IRS‑1/2, PI3K, AKT, GLUT4, and AMPK pathways are all dysregulated.
- Mitochondrial dysfunction and oxidative stress further impair glucose disposal.