Inflammatory mechanisms in the regulation of insulin resistance

Abstract

Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. It has been demonstrated that IR is associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-alpha), interleukin (IL)-1, IL-6, and various adipocytokines. Furthermore, several transcription factors and kinases such as c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase-beta (IKKbeta), a kinase located proximal of nuclear factor-kappaB (NF-kappaB), participate in this process. Hepatocyte-specific overexpression of NF-kappaB is associated with IR and can mimic all features of fatty liver disease. Whereas the evidence for an important role of many pro-inflammatory pathways in IR in in vitro and animal studies is overwhelming, data from interventional studies in humans to prove this concept are still minor. As a complex network of inflammatory cytokines, adipocytokines, transcription factors, receptor molecules, and acute-phase reactants are involved in the development of IR, new therapeutic approaches in IR-related diseases will be based on a better understanding of their complex interactions.

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-αwas among the first mediators defined as a key factor linking inflammation, obesity, and IR. Engagement of TNFR by TNF-αinduces inhibitory phosphorylation of serine residues of IRS-1 and activates IKKβ/NF-κB and JNK pathways, two major intracellular regulators of IR. Moreover, TNF-αantagonizes 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.