Insulin Resistance and Endothelial Function in Cardiovascular Health

Insulin exerts powerful vasodilatory effects through its action on the vascular endothelium, primarily by stimulating endothelial nitric oxide synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway to produce nitric oxide (NO). In states of insulin resistance, this metabolic signalling cascade becomes blunted, reducing NO bioavailability, impairing vasodilation and tipping the balance towards vasoconstrictor influences such as endothelin-1. Endothelial dysfunction arising from impaired insulin action contributes to hypertension, atherogenesis and microvascular complications, and underpins much of the cardiovascular risk in type 2 diabetes and metabolic syndrome. At the same time, compensatory hyperinsulinaemia can activate alternative mitogenic pathways—most notably Ras/MAPK—which promote inflammation, adhesion molecule expression and smooth muscle proliferation. Factors such as elevated free fatty acids, chronic hyperglycaemia and oxidative stress further disrupt endothelial insulin signalling by up-regulating phosphatases (for example PTEN) or activating serine kinases that phosphorylate insulin receptor substrates on inhibitory sites. The result is a vicious circle in which reduced capillary recruitment limits tissue perfusion and nutrient delivery, exacerbating systemic insulin resistance. Understanding these intertwined mechanisms has global significance, as it informs lifestyle interventions, pharmacological strategies and the development of novel agents aimed at restoring endothelial insulin sensitivity and reducing cardiovascular events in at-risk populations.

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Insulin Resistance and Endothelial Function in Cardiovascular Health publication trend

The graph below shows the total number of articles in insulin resistance and endothelial function in cardiovascular health across all publications each year (not limited to Nature Index journals).

Technical terms

Insulin resistance: A diminished cellular response to insulin resulting in impaired glucose uptake and signalling.

Endothelial function: The capacity of the vascular endothelium to regulate vasodilation, thrombosis and inflammation.

Endothelial nitric oxide synthase (eNOS): An enzyme in endothelial cells that produces nitric oxide, a key vasodilator.

Phosphatidylinositol 3-kinase (PI3K): A lipid kinase that initiates downstream signalling leading to Akt activation and eNOS phosphorylation.

Akt (protein kinase B): A serine/threonine kinase that phosphorylates eNOS and other targets to mediate metabolic and survival signals.

Phosphatase and tensin homolog (PTEN): A lipid phosphatase that dephosphorylates PI3K products, antagonising insulin signalling.

References

1. Insulin-stimulated Activation of eNOS Is Independent of Ca2+ but Requires Phosphorylation by Akt at Ser1179 *. Journal of Biological Chemistry (2001).
2. Free Fatty Acids Inhibit Insulin Signaling–Stimulated Endothelial Nitric Oxide Synthase Activation Through Upregulating PTEN or Inhibiting Akt Kinase. Diabetes (2006).
3. Short-term high glucose exposure impairs insulin signaling in endothelial cells. Cardiovascular Diabetology (2015).
4. Hyperinsulinemia augments endothelin‐1 protein expression and impairs vasodilation of human skeletal muscle arterioles. Physiological Reports (2016).