MAPT and Insulin resistance: On the one hand, brain insulin resistance reduces the serine phosphorylation of insulin receptor substrate 1, protein kinase B phosphorylation through cascade reactions, and diminished phosphorylation of c-Jun amino-terminal kinase (JNK), which in turn impacts insulin pathway components such as glycogen synthase kinase-3 and protein kinase A. The insulin signaling pathway may be activated by changes in the activity of certain downstream components, which can promote tau protein hyperphosphorylation and neurofibrillary tangle development.