3.1.1. Canonical Insulin Signaling

The classical mechanism of action in insulin signaling has been extensively described and reviewed [63–65]. Briefly, the binding of insulin to its receptor (IR) in target tissues promotes tyrosine autophosphorylation, recruiting IR substrates as the IRS and Shc proteins. Shc activates the Ras/MEK/ERK pathway, which accounts for mostly the growth-promoting effects of insulin. On the other hand, IRS1 and IRS2 continue the PI3K/Akt/mTOR pathway. IRS proteins recruit the p85 regulatory domain of phosphatidylinositol 3 kinase (PI3K), leading to phosphatidylinositol-3,4,5-triphosphate (PIP3), and activating the phosphorylation of Akt (also known as PKB). Full activation of Akt needs complementary phosphorylation by mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Akt then mediates most of the insulin effects, as it phosphorylates and inhibits glycogen synthase kinase 3-β (GSK3-β), preventing the inhibition of glycogen synthase (GS) and leading to increased glycogen synthesis. Akt also promotes glucose uptake by the mobilization of glucose transporter 4 (GLUT4) and activates the mTOR complex 1 (mTORC1) via inhibition of tuberous sclerosis 1 (TSC1) and 2 (TSC1), leading to protein and lipid synthesis. Insulin signaling is a more complex process that involves major proteins that participate in the glucogenic pathway, such as fructose 2,6-bisphosphatase (FBPase-2), or the lipogenic pathway, like hormone-sensitive lipase (HSL), which are negatively regulated by protein kinase A (PKA) and also inactivated by Akt.
