Figure 1.

Insulin Signaling in Insulin-responsive Cell. In healthy individuals, insulin binds to the ectodomain of IRs, causing a conformational change that leads to the autophosphorylation of the tyrosine residues in the cytoplasmic β subunits. The IRS then binds to the phosphorylated tyrosine residues of IRs, causing them to be phosphorylated. Phosphorylated IRSs bind to PI3K, and as a consequence, PI3K is activated and converts PIP2 to PIP3. PIP3 recruits the serine/threonine kinase Akt (also known as protein kinase B) to the plasma membrane, where it is activated by phosphorylation. The activated Akt is responsible for the translocation of GLUT4 to the plasma membrane, allowing the entry of glucose into the cell, which will be used to produce ATP through mitochondrial oxidative phosphorylation. Activated Akt also promotes the inhibition of GSK3B, which leads to higher glycogen synthesis. Once activated, Akt also inhibits transcription factor FOXO1, which promotes transcription of lipoprotein lipase, an enzyme responsible for the breakdown of triglycerides. Furthermore, phosphorylated Akt inhibits TSC1/2, and as a consequence, mTORC1 is activated, which leads to protein synthesis. Activation of S6K1 by mTORC1 phosphorylates inhibitory serine residues on the IRS, while mTORC1-induced activation of GRB10 prevents insulin signaling by binding to IR. (Created with BioRender.com on 19 October 2022). Abbreviations: IRs, insulin receptors; IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase; PDK1, 3-phosphoinositide-dependent protein kinase 1; PIP₂, phosphatidylinositol 4,5-biphosphate; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; GLUT4, glucose transporter type 4; GSK3B, glycogen synthase kinase 3β; FOXO1, forkhead box O; TSC1/2, tuberous sclerosis protein complex 1 and 2; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; S6K1, S6 kinase 1; GRB10, growth-factor-receptor-bound protein 10.