Further note, unlike IRS‐1/PI3K, activation of IRS‐2 and IRS‐2/PI3K in both muscle and liver is resistant to downregulation in DIO/MetS/T2DM17, 18, 19, 20 (Figure 1) and is responsive to hyperinsulinemia.18, 19, 20, 21. The gene discussed is IRS1; the disease is hyperinsulinism.