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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAvc4AX5Av8x7c4ez5dvXkjfErYnq2IGUcqxmcrYlB2ds#_3 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAvc4AX5Av8x7c4ez5dvXkjfErYnq2IGUcqxmcrYlB2ds#_2 http://www.w3.org/ns/prov#value Yuan et al. (87) first hypothesized and then demonstrated that salicylate treatment improves the severe insulin resistance seen in genetically obese rodents. Furthermore, pretreatment in rats with salicylates prevented lipid-induced skeletal insulin resistance by inhibiting lipid-induced decreases in insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI 3-kinase activation (88). In humans, treatment with high doses of aspirin (7 g/day) or salsalate (3 g/day) improved peripheral insulin sensitivity in subjects with type 2 diabetes (96,97). Although these results are intriguing, randomized controlled trials are needed to clarify the role of these drugs on glucose metabolism and insulin resistance. Other drugs with documented anti-inflammatory effects, such as thiazolidinediones (TZDs) and statins, have shown antidiabetic effects. TZDs are potent insulin sensitizers, and TZD treatment has been associated with suppression of local TNF-alpha production by adipocytes and reduction of TNF-alpha action in adipose and other tissues (98). TZDs can also act by increasing plasma levels of adiponectin, and some studies have suggested that peroxisome proliferator- activated receptor gamma (like peroxisome proliferator- activated receptor alpha) activation in selected cell types can repress NF-kappaB and, therefore, cytokine-mediated signaling (98). Statins are potent cholesterol-lowering drugs. Statin treatment has been associated with modulation in the endothelial adhesion and transendothelial migration of leukocytes, inhibition of the release of cytokines, and chemokines and direct interference with the NF-kappaB pathway (99). Interestingly, the use of statins has also been associated with a decrease in the risk of developing type 2 diabetes (100). We have discussed how activation of protein kinases and transcription factors, such as AP-1 and NF-kappaB, are possible mediators of insulin resistance in peripheral tissues. Because the same molecules are directly involved in beta-cell apoptosis (101), it is possible that an adipokineinduced activation of the immune system associated with overnutrition and obesity may also explain the beta-cell failure that precedes the development of type 2 diabetes. Here, data from the literature do not paint a very clear picture. For example, adiponectin has been shown in vitro to have protective effects against both cytokine- and FFA-induced impairment of the beta-cell (102), an effect that would be lost in obese individuals with hypoadiponectinemia. Leptin, which is very high in obese individuals, has been shown in vitro to have both stimulatory and inhibitory effects on beta-cell apoptosis (103). More important, thus far there are no reports in the literature from in vivo animal or human studies of an independent association between (markers of) inflammation and beta-cell dysfunction. IS EXCESSIVE FATNESS AN OBLIGATORY PATHOPHYSIOLOGICAL FACTOR? While we have developed this review around the pathophysiological construct that overnutrition leads to obesity which in turn is associated with a chronic activation of the immune system, we would like to acknowledge experimental and circumstantial evidence that challenges this course of events. 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