Since Nrf2 overactivation is likely a primary output of increased IIS in metabolic disorders (e.g., obesity), our observation that CncC/Nrf2 OE‐induced diabetic phenotypes can be mitigated by early constant lowering of IIS or by modulating IIS downregulation end points (e.g., ALP activation or Gys inhibition) is of particular importance. The gene discussed is GYS1; the disease is obesity disorder.