FIG. 4.

Autophagy is regulated by upstream insulin signaling and energy-sensing pathways. Insulin receptor activation activates the PI3K/PDK/AKT pathway, which inhibits autophagy by multiple mechanisms. AKT-mediated phosphorylation of FOXO transcription factors prevents their translocation to the nucleus, thereby suppressing transcription of autophagy-related genes. AKT activation also leads to activation of the mTORC1 complex, which inhibits autophagy by blocking activation of ULK1/2 and BECLIN1. BCL-2 participates in inhibiting BECLIN1 activity by directly binding BECLIN1. Disruption of insulin signaling by polyol pathway products could interfere with insulin receptor signaling, resulting in aberrant autophagy activation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars