However, very few peripheral insulin can access the brain through the BBB in T2D due to the hyperinsulinemia and brain insulin resistance (Arnold et al. 2018; El Khoury et al. 2014; Freude et al. 2005), which was also proven in our animal experiments, as subcutaneous insulin injection failed to remarkably increase the insulin level in CSF (Figs. 2B, 3B). Here, INS is linked to hyperinsulinism.