Fig. 3.

Inhibition of the insulin signaling pathway by oxidative stress. Reactive oxygen species (ROS) interferes with insulin action by altering several substrates of the insulin signaling pathway. ROS activates serine/threonine kinases, including protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and inhibitory κB kinase (IKK), which not only inhibit the activation of insulin receptor substrate (IRS) through serine phosphorylation but also induce inflammation by activating nuclear factor κB (NF-κB). In addition, ROS suppresses glucose absorption by degrading glucose transporter type 4 (GLUT4) in a casein kinase 2 (CK2)-dependent manner. Reactive nitrogen species (RNS) inhibits tyrosine phosphorylation of IRS and protein kinase B (AKT) activation by inducing nitration of tyrosine. Mitochondrial functional defects by ROS not only induce an explosive increase in oxidative stress but also suppress mitochondrial energy production, eventually leading to cell death. Tyr, tyrosine; Ser, serine; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol (3,4,5)-triphosphate; PI3K, phosphatidylinositol 3-kinases; PDK1, phosphatidylinositide-dependent protein kinase 1; mTORC2, mammalian target of rapamycin complex 2; FOXO1, forkhead box protein O1; GSK3, glycogen synthase kinase 3; AS160, AKT substrate of 160 kDa; acetyl-CoA, acetyl coenzyme A; mtDNA, mitochondrial DNA; TCA, tricarboxylic acid cycle; ETC, electron transport chain.