The metabolic functions of insulin are primarily reflective of its role in glucose and lipid homeostasis in skeletal muscle, adipose tissue, and liver. However, insulin also exerts important functions in other non-classical insulin target tissues such as the brain, pancreas, and the vascular endothelium. The ability of insulin to exert vasodilator action in the vascular endothelium as a result of increased nitric oxide (NO) production is an important component of the ability of this hormone to enhance glucose uptake by skeletal muscle. The insulin-mediated signaling pathway that triggers production of NO in vascular endothelium involves the same signaling proteins (PI3K, PKD, and PKB/AKT) that are components of metabolic regulatory pathways induced by insulin. Therefore, it is understandable why the same disruptions to insulin signaling that lead to IR (see above) caused by excess FFAs and hyperglycemia result in endothelial dysfunction.
The production of NO in endothelial cells is the result of the activation of endothelial nitric oxide synthase (eNOS). The production and actions of NO and the various NOSs involved are discussed in more detail in the Amino Acid Derivatives page. With respect to insulin action, the activation of endothelial PKB/AKT leads to phosphorylation and activation of eNOS and thus increased NO production. In addition to modulating vascular tone by activating signaling events in the underlying vascular smooth muscle cells, endothelial cell-derived NO reduces the production of pro-inflammatory cytokines, reduces leukocyte and monocyte recruitment and adhesion to the endothelium, inhibits the proliferation of vascular smooth muscle cells, inhibits apoptosis, and attenuates platelet aggregation. Inactivation of endothelial cell NO production, as occurs due to IR, results in endothelial dysfunction and promotes the development of atherosclerosis. As described above for the liver and adipose tissue, elevated levels of circulating FFAs lead to impaired insulin signaling via the PI3K-PDK-PKB/AKT pathway in vascular endothelial cells.
Insulin exerts its mitogenic, growth promoting, and differentiation effects via a signaling pathway that involves mitogen-activated protein kinase (MAPK) which is distinct from the PI3K-PDK-PKB/AKT pathway that is involved in metabolic regulation by insulin. The MAPK-induced pathway does not play a role in the production of NO by insulin. This MAPK-induced pathway plays a significant role in the development of atherosclerosis in the IR state. When insulin signaling via PI3K-PDK-PKB/AKT is impaired as described above for the IR state, the MAPK signaling pathway in endothelial cells is enhanced. In the endothelium MAPK activation by insulin results in increased expression of endothelin-1 (ET-1), plasminogen activator inhibitor type-1 (PAI-1), and the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. ET-1 is a potent vasoconstrictor and contributes to endothelial cell dysfunction in the presence of IR. The increased expression of numerous cell adhesion molecules accelerates the adherence to the endothelium of pro-inflammatory leukocytes which in turn contributes to the development of atherosclerosis. Therefore, the molecules beneficial to vascular endothelial health that are induced by insulin (e.g. NO) are reduced in the IR state and those that are proatherogenic (e.g. ET-1, PAI-1) are increased.