INS and Hypoglycemia: To further ascertain more about long-term hyperglycemia and recurrent hypoglycemia-induced changes in insulin-linked signaling activities in brain cortical tissue, we decided to evaluate the protein levels of insulin (IR) and IGF-1 receptor (IGF-1R); the catalytic subunit of PI3K; and the P13K (p110) protein (Figure 6), and the activation status of its canonical downstream mediators, the PI3K/Akt and mitogen-activated protein kinase (MAPK/ERK1/2) pathways (Figure 7).