In insulin-resistant states, pro-inflammatory cytokines, such as TNF-α and IL-6, induce serine phosphorylation of IRS-1, inhibiting PI3K/AKT signaling and exacerbating hyperglycemia.28 This leads to oxidative stress via ROS and PKC activation, compromising LEC integrity, increasing vascular permeability, and promoting inflammation hallmarks of lymphedema.32 Additionally, insulin resistance accelerates the formation of AGEs, which engage the RAGE, activating NF-κB. Here, IRS1 is linked to Insulin resistance.