Figure 8.

Schematic representation of insulin resistance-mediated mechanisms in LECs. Under normal physiologic conditions, insulin stimulates eNOS phosphorylation via PI3K/Akt signaling that regulates NO production. LEC junctions are well regulated via adherens junctions in the normal state, thus maintaining lymphatic function. However, the onset of insulin resistance impairs the PI3K/Akt/eNOS pathway, diminishing NO production, and impairs mitochondrial function in LECs. These mechanisms further disrupt the endothelial membrane integrity by disrupting the adherens junction and thus increase LEC permeability and activate proinflammatory signaling, together leading to impaired lymphatic function.