IRS2 is a cytoplasmic adaptor protein that mediates insulin and IGF1 receptor signaling, playing central roles in metabolic homeostasis, growth, and cellular stress responses 1. Upon insulin receptor phosphorylation, IRS2 recruits SH2 domain-containing proteins including PI3K, GRB2, and SHP2, activating both the PI3K/AKT pathway (responsible for metabolic effects) and the Ras/MAPK cascade (regulating gene expression and cell proliferation) 23. IRS2 also positively regulates Wnt/β-catenin signaling and promotes spindle assembly checkpoint function during mitosis 45. Dysregulation of IRS2 signaling has broad disease relevance. Male Irs2-deficient mice develop type 2 diabetes, demonstrating IRS2's critical role in glucose homeostasis 6. Loss of IRS2 signaling contributes to diabetic complications including nephropathy, neuropathy, and retinopathy 6. Beyond metabolism, cardiac IRS2 protects against stress-induced arrhythmias by restraining AKT/NOS3/CaMKII/RyR2 signaling and maintaining calcium homeostasis 7. IRS2 also regulates chondrocyte autophagy and mitochondrial function in osteoarthritis prevention 8, and IRS2 amplification promotes β-catenin activation and brain metastases in colorectal cancer 9. Therapeutically, increasing IRS2 expression in pancreatic β cells enhances glucose tolerance and reduces diabetes progression 10.