IRS1 and Insulin resistance: Mutations in the IRS1 gene are closely linked to insulin resistance.464 In patients with T2D, the G972R polymorphism of IRS-1 is observed with higher frequency, leading to reduced insulin signaling, primarily due to decreased PI3K activity.465 Further studies have shown an association between IRS-1 mutations and SNPs in T2D.466 Mice with an Irs-1 gene knockout exhibit growth retardation and insulin signaling defects.467 Phosphorylation site mutations in IRS1 can disrupt the interaction with IR, thereby weakening PI3K activation, resulting in impaired AKT signaling.