IRS1 and Hyperglycemia: Under physiological conditions, insulin binds its receptor, activating IRS-1, which propagates signals through the PI3K/AKT pathway, essential for glucose uptake via GLUT4 translocation to the cell membrane.27 In insulin resistance, pro-inflammatory cytokines, such as TNF-α and IL-6, promote serine phosphorylation of IRS-1, impairing its interaction with PI3K and disrupting AKT signaling, leading to reduced glucose uptake and exacerbated hyperglycemia.28,29 Chronic hyperinsulinemia aggravates LEC dysfunction, critical for lymphatic vessel integrity.