Insulin Signaling Pathway

IR is a heterotetrametric transmembrane glycoprotein composed of α2β2 and is a casein kinase receptor. The α-subunit located outside the membrane binds to insulin, causing the conformational change of the receptor to cause autophosphorylation of a specific tyrosine residue on the β subunit, and the tyrosine phosphorylated β subunit further increases its kinase activity. A series of IRS1~4 proteins were recruited and phosphorylated, with IRS1 and IRS2 being the most widely expressed. The tyrosine phosphorylated IRS protein recruits and binds to a SH2 domain-containing signaling molecule that activates two signal transduction pathways in the cell: 1) phosphatidylinositol-3-kinase(PI3K)-protein kinase B(Akt or PKB) pathway: phosphorylated IRS protein then binds to the P85 subunit of PI3K and recruits its catalytic subunit P110 to activate PI3K; PI3K activates phosphorylation of phosphatidylinositol to produce 3,4,5-phosphatidylinositol-3,4,5-triphosphate (PIP3), which in turn activates the serine/threonine protein kinase Akt that activates a variety of substrates and mediates multiple organisms of insulin effect. For example, by monophosphorylation of AS160, glucose transporter 4(GLUT4) is translocated to the cell membrane to uptake glucose; phosphorylation of glycogen synthase kinase 3(GSK3) inhibits GSK3 activity, increases the activity of glycogen synthase, promotes cellular uptake of glucose and synthesis of glycogen, and lowers blood glucose; Phosphorylation of the transcription factor, fork head box protein O1(FOXO1), inactivates and degrades FOXO1, and inhibits phosphoenolpyruvate carboxykinase(PEPCK) and its key enzyme of gluconeogenesis. Then the transcriptional regulation of glucose-6-phosphatase(G6Pase) inhibits hepatic gluconeogenesis and lowers blood glucose, activates mammalian target ofrapamycin(mTOR), promotes protein synthesis and cell growth, etc. The metabolic function of insulin is to be carried out through this branch. 2) Ras-mitogen-activated protein kinase(MAPK) pathway: the growth signaling pathway. Mammalian MAPK families include p38, extracellular-signal-regulated kinase(ERK) and c-Jun N-terminal kinase(JNK). IRS1/2 activates MAPK by binding to growth factor receptor-bound protein 2(Grb2), regulates gene transcription and regulates cell proliferation and differentiation by interacting with PI3K-AKT pathway. IRS acts as the intersection of the two signal pathways, and the signaling pathways mediated by different subtypes are also different. In the liver, insulin receptor substrate(IRS1) and insulin receptor substrate 2(IRS2) mediate lipid production and glycogen synthesis, respectively, and IRS2-mediated signaling pathways are impaired during insulin resistance, while the IRS1-mediated signaling pathway is relatively intact. Insulin resistance in skeletal muscle appears to primarily attenuate IRS1-mediated signaling pathways for GLUT4 transport and glucose uptake, although some studies have also shown that IRS2-mediated signaling pathways are also involved in glucose metabolism.