Inflammatory mechanisms in the regulation of insulin resistance.
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.
Tilg
Herbert
H
Department of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria. herbert.tilg@i-med.ac.at
Moschen
Alexander R
AR
D000209:Acute-Phase Proteins / Q000276:immunology; D017667:Adipocytes / Q000378:metabolism; D054392:Adipokines / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D050556:Fatty Acid-Binding Proteins / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007333:Insulin Resistance / Q000276:immunology* / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D053495:Osteopontin / Q000276:immunology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism
D000209:Acute-Phase Proteins; D054392:Adipokines; D000893:Anti-Inflammatory Agents; D018925:Chemokines; D016207:Cytokines; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D047495:PPAR gamma; D014157:Transcription Factors; D053495:Osteopontin; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases