insulinPI3KAKTmTOR

The insulin-PI3K-AKT-mTOR pathway, also referred to as the insulin signaling pathway through PI3K/AKT/mTOR, is a central intracellular cascade triggered by insulin binding to the insulin receptor. Activation leads to tyrosine phosphorylation of IRS proteins, recruitment of PI3K, conversion of PIP2 to PIP3, and recruitment of PDK1 and AKT to the membrane. AKT is activated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2.

Active AKT promotes glucose uptake via GLUT4 translocation, stimulates glycogen synthesis, and inhibits apoptosis. It also modulates protein synthesis by inhibiting the TSC1/TSC2 complex, enabling Rheb-GTP to activate mTORC1. mTORC1 promotes protein synthesis through S6K1 and 4E-BP1 and inhibits autophagy under nutrient-replete conditions. mTORC1 activity is further regulated by amino acids via Rag GTPases and by cellular energy status via AMPK; there is also negative feedback through S6K1 that can dampen insulin signaling by phosphorylating IRS-1.

Physiological roles of the insulin-PI3K-AKT-mTOR axis include regulation of glucose metabolism, cell growth, and autophagy, making it essential for metabolic homeostasis and normal growth. Dysregulation is linked to insulin resistance, type 2 diabetes, obesity, and cancer. Mutations and alterations in pathway components (such as PIK3CA activation or PTEN loss) can drive oncogenesis. Therapeutic approaches target this axis at multiple levels, including mTOR inhibitors (rapamycin and analogs) and various PI3K and AKT inhibitors, reflecting the pathway’s broad clinical significance and the potential for side effects due to its central role in physiology.