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. Here, IRS1 is linked to Hyperinsulinemia.