Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.
Steven E. Shoelson, Jongsoon Lee, Allison B. Goldfine
Potential cellular mechanisms for activating inflammatory signaling.
Obesity and high-fat diet activate IKKβ/NF-κB and JNK pathways in adipocytes, hepatocytes, and associated macrophages. Stimuli that have been shown to activate these pathways during metabolic dysregulation include ligands for TNF-α, IL-1, Toll, or AGE receptors (TNFR, IL-1R, TLR, or RAGE, respectively), intracellular stresses including ROS and ER stress, ceramide, and various PKC isoforms. Obesity-induced IKKβ activation leads to NF-κB translocation and the increased expression of numerous markers and potential mediators of inflammation that can cause insulin resistance. Obesity-induced JNK activation promotes the phosphorylation of IRS-1 at serine sites that negatively regulate normal signaling through the insulin receptor/IRS-1 axis. Examples include serine-302 (pS302) and serine-307 (pS307). By contrast, evidence has not been reported for obesity-induced effects on transcription factors such as AP-1 that are regulated by JNK. IKKβ and/or NF-κB are inhibited or repressed by the actions of salicylates, TZDs, and statins.
Copyright © 2014 American Society for Clinical Investigation