GYS1 and obesity due to melanocortin 4 receptor deficiency: 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.