Fig. 2.

Mechanistic association of insulin signaling with mitochondrial function in normal and diabetic brain. Schematic outline of neuronal insulin signaling in the normal brain (a) and in the diabetic brain (b). In physiological conditions, insulin binding to its receptor at the synapse triggers phosphorylation of IRSs, PI3K activation, Akt phosphorylation, inhibits the transcriptional factor FOXO1, and promotes the AMPK-SIRT1-PGC-1α mediated Mt metabolic pathway. In the diabetic brain, insulin resistance and impaired insulin signaling reduces signaling in these pathways and decreases the stability of Mt electron transport proteins thereby increasing oxidative stress. Insulin resistance impairs the electron transport chain, reducing ATP and NAD⁺ generation, and inhibits activation of the NAD⁺-dependent deacetylase SIRT1. Inactivation of SIRT1 further reduces Mt function and repair. As in Fig. 1, the reduction in brain insulin signaling also increases GSK-3b activity that increases abnormal tau phosphorylation