Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

Figure 2 The potential pathways mediate the enhancement of the Nrf2 system on insulin signaling transduction. As a protective machinery, Nrf2 activation promotes the expression of a variety of key anti-oxidative enzymes that scavenge reactive oxidative species, attenuate oxidative stress-induced inflammatory activation, mitochondrial damage and ER stress. Subsequently, Nrf2 enhances insulin signaling by blocking the activation of IKKβ, PKC and JNK, respectively, that promotes the serine phosphorylation of IRS-1 and impairs the tyrosine phosphorylation of IRS-1 as well as subsequent insulin signaling transduction[28]. Furthermore, Nrf2 may directly enhance insulin signaling by an unidentified mechanism[15]. On the other hand, insulin signaling components, such as GSK-3 or mTOR, can promote Nrf2 function by regulating its content and nuclear location[49,50]. The Nrf2 activation, particularly the Nrf2-targeted gene products, heme oxygenase-1 and Mn-SOD, protects from oxidative stress-induced abnormalities and exerts a sensitizing action on insulin signaling[51,52]. ARE: Antioxidant response element; ER: Endoplasmic reticulum; GSK: Glycogen synthesis kinase; GST: Glutathione S-transferase; HO-1: Heme oxygenase-1; iNOS: Inducible nitric oxide synthase; IKK: Inhibitor of κB kinase; IRS: Insulin receptor substrate; JNK: C-Jun N-terminal kinase: mTOR: Mammalian target of rapamycin; Mn-SOD: Mn-superoxide dismutase; Nrf2: Nuclear factor (erythroid-derived 2)-like 2; PKB: Protein kinase B; PKC: Protein kinase C; TNFα: Tumor necrosis factor-α.