Energy deprivation inhibits Akt

The paper below shows that both energy depletion and oxidative stress downregulate IRS-1 activation by phosphorylation of Ser-794 site.

This may may explain why OCD symptoms increase in between meals in our case - glucose returns to basal level, at the same time sensitivity of the cells to glucose is lower due to deactivation of IRS-1, and PI3K/Akt pathway is less active (or shut down) which allows GSK3b to inhibit Nrf2, leading to increased oxidative stress.

Energy depletion activates AMP-activated protein kinase (AMPK) and inhibits cell growth via TSC2-dependent suppression of mTORC1 signaling.

Long term energy depletion also induces apoptosis by mechanisms that are not well understood to date. Here we show that AMPK, activated by energy depletion, inhibited cell survival by binding to and phosphorylating IRS-1 at Ser-794.

Phosphorylation of IRS-1 at this site inhibited phosphatidylinositol 3-kinase/Akt signaling, suppressed the mitochondrial membrane potential, and promoted apoptosis.

Of the treatments promoting energy depletion, glucose deprivation, hypoxia, and inhibition of ATP synthesis in the mitochondria stimulated phosphorylation of IRS-1 at Ser-794 via an LKB1/AMPK-dependent manner, whereas oxidative stress and 2-deoxyglucose stimulated phosphorylation at this site via a Ca2+/calmodulin-dependent protein kinase kinase β/AMPK axis.