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. The gene discussed is INS; the disease is Insulin resistance.