Inflammation and insulin resistance 10.1016/j.febslet.2007.11.057 : FEBS Letters | Scie... - 0 views
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inflammation insulin resistance IR PPAR TNF-alpha IL-6 IL-10 IL-1Beta JNK GLT-4 Resistin adiponectin Gherlin NF-kapppB iNOS lkkb obesity TLR-4
shared by Nathan Goodyear on 10 Jan 12
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A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
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Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
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Insulin is a pleiotropic hormone
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the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
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Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
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Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
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adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
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One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
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The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
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elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
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overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
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Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
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In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
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macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
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saturated fatty acids are the most potent inducers of this inflammatory response
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Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
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Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
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In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
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elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
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Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
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C-reactive protein (CRP)
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these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
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the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
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It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
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Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
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Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
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Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
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Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
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Great review of all the known components in the inflammation, insulin resistance link