While we are now aware of many of the inflammatory factors that mediate insulin resistance and have some understanding of the intracellular pathways involved, there is still much that remains poorly understood. Crucial questions that are currently open regard the initiation of the inflammatory response. Is inflammation the primary event linking obesity with insulin resistance, or does the inflammatory response begin only after the onset of resistance to insulin? How and why does the body initiate an inflammatory response to obesity? Does obesity per se induce an inflammatory response, or is inflammation initiated as a secondary event by hyperlipidemia or hyperglycemia?
In reviewing the facts, it is fairly clear that obesity promotes states of both chronic low-grade inflammation and insulin resistance. However, even in the absence of obesity, infusion of animals with inflammatory cytokines or lipids can cause insulin resistance (54
). Additionally, humans with some other chronic inflammatory conditions are at increased risk for diabetes; for example, about one-third of patients with chronic hepatitis C develop type 2 diabetes, and elevated TNF-α levels are implicated in this link (95
). Rheumatoid arthritis also predisposes patients to diabetes and particularly cardiovascular disease, and some evidence indicates a link between inflammatory lung diseases and risk of cardiovascular disease and diabetes (97
). Finally, removal of inflammatory mediators or pathway components, such as TNF-α, JNK, and IKK, protects against insulin resistance in obese mouse models, and treatment of humans with drugs that target these pathways, such as salicylates, improves insulin sensitivity (6
). Thus, the available evidence strongly suggests that type 2 diabetes is an inflammatory disease and that inflammation is a primary cause of obesity-linked insulin resistance, hyperglycemia, and hyperlipidemia rather than merely a consequence (Figure ).
Figure 3 Nutrient and pathogen sensing or response systems have important overlapping features, and their modulation by obesity or infection can lead to overlapping physiological outcomes. For example, the chronic inflammation of obesity leads to elevated plasma (more ...)
But how does the inflammatory response begin? Though this question cannot currently be answered, we can suggest some reasonable speculations based on the available data. It seems likely that the inflammatory response is initiated in the adipocytes themselves, as they are the first cells affected by the development of obesity, or potentially in neighboring cells that may be affected by adipose growth. How might expanding adipocytes trigger an inflammatory response?
One mechanism that, based on newly emerging data, appears to be of central importance is the activation of inflammatory pathways by ER stress. Obesity generates conditions that increase the demand on the ER (39
). This is particularly the case for adipose tissue, which undergoes severe changes in tissue architecture, increases in protein and lipid synthesis, and perturbations in intracellular nutrient and energy fluxes. In both cultured cells and whole animals, ER stress leads to activation of JNK and thus contributes to insulin resistance (39
). Interestingly, ER stress also activates IKK and thus may represent a common mechanism for the activation of these 2 important signaling pathways (100
A second mechanism that may be relevant in the initiation of inflammation in obesity is oxidative stress. Due to increased delivery of glucose to adipose tissue, endothelial cells in the fat pad may take up increasing amounts of glucose through their constitutive glucose transporters. Increased glucose uptake by endothelial cells in hyperglycemic conditions causes excess production of ROS in mitochondria, which inflicts oxidative damage and activates inflammatory signaling cascades inside endothelial cells (101
). Endothelial injury in the adipose tissue might attract inflammatory cells such as macrophages to this site and further exacerbate the local inflammation. Hyperglycemia also stimulates ROS production in adipocytes, which leads to increased production of proinflammatory cytokines (42