IRS1 is a critical signaling adapter protein that mediates insulin receptor and IGF-1 receptor signaling, playing essential roles in glucose homeostasis and metabolic regulation 123. Upon insulin receptor phosphorylation, IRS1 recruits SH2 domain-containing proteins including the p85 regulatory subunit of PI3K, GRB2, and SHP2, propagating signals through both the PI3K/AKT and Ras/MAPK pathways 45. The PI3K/AKT pathway mediates insulin's metabolic effects on glucose uptake and glycogen synthesis, while MAPK signaling regulates gene expression and cell growth 6. IRS1 also positively regulates Wnt/beta-catenin signaling through DVL2 modulation 7. IRS1 dysfunction is strongly associated with type 2 diabetes pathogenesis. Genetic variants, including the rs1801278 polymorphism, show significant association with T2DM susceptibility 8, and high-risk variants can compromise protein structural stability and signaling capacity 9. In insulin resistance, selective impairment of IRS1 signaling occurs in tissues like kidney and liver, while IRS2 pathways may remain preserved, contributing to hyperglycemia and altered lipid metabolism 10. IRS1 promoter methylation inversely correlates with gene expression and associates with adverse metabolic traits 11. Additionally, IRS1 variants contribute to gestational diabetes mellitus susceptibility through effects on insulin secretion and peripheral signaling 12, and polymorphisms associate with autism spectrum disorder, highlighting IRS1's broader role in IGF pathway-dependent development 13.