Figure 1

Regulation of IR: involved mediators and pathways. In recent years, several inflammatory pathways involved in the generation/regulation of IR have been identified. TNF-α was among the first mediators defined as a key factor linking inflammation, obesity, and IR. Engagement of TNFR by TNF-α induces inhibitory phosphorylation of serine residues of IRS-1 and activates IKKβ/NF-κB and JNK pathways, two major intracellular regulators of IR. Moreover, TNF-α antagonizes adiponectin, an important insulin-sensitizing adipocytokine that signals via adiporeceptors. IL-1 and IL-18 are also able to induce IR. IL-1 has been shown to reduce IRS-1 expression via ERK1/2 and can activate the IKKβ/NF-κB pathway. A role for IL-18 in the regulation of IR has recently been demonstrated in IL-18^−/− and IL-18R^−/− mice. IL-6 is another cytokine involved in the generation of IR. This cytokine can induce SOCS1 and SOCS3 that link IRS to ubiquitin-mediated degradation. ER stress as well as oxidative stress are both involved in inflammation-associated IR. An important role for the IKKβ/NF-κB pathway has been demonstrated in experiments where knocking out or knocking down of IKKβ or JNK protected mice from IR.