We show that NF-κB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-κB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-β in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1β and TNF-α, was increased in LIKK mice to a similar extent as induced by HFD in in wildtype mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-β. Hepatic expression of the IκBα superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-κB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.Obesity is increasingly prevalent and strongly associated with the development of insulin resistance 1 , an underlying feature of both type 2 diabetes (T2D) and the metabolic syndrome 2 . Although epidemiological correlations are established, the cellular and molecular mechanisms that link obesity and insulin resistance are unknown. Increased adiposity is associated with lipid accumulation in other tissues, including muscle (intramyocellular lipid) and liver (hepatic steatosis), which has made it that much more difficult to pinpoint the primary sites responsible for initiating insulin resistance 3 . Fat accumulation in the visceral depot and liver are strongly correlated, and both are highly correlated with the development and severity of insulin resistance 4-6 .Growing evidence links a chronic, subacute inflammatory state to the development of obesity and the coexisting conditions of insulin resistance, T2D and the metabolic syndrome. Epidemiologists have consistently found elevations in markers and potential mediators of inflammation and the acute-phase response 7,8 , suggesting that low-grade inflammation precedes and predicts the development of T2D 9 . Proinflammatory cytokines can cause insulin resistance 10,11 and anti-inflammatory medications may reverse it 12,13 , suggesting that inflammation may be directly involved in its pathogenesis. Markers and mediators of inflammation that are biosynthesized in liver include CRP, PAI-1, fibrinogen and IL-6, suggesting that 'subacute inflammation' in liver, secondary to steatosis, might be involved in the development of insulin resistance, T2D and the metabolic syndrome. Because visceral adiposity and hepatic steatosis are etiologically and functionally intertwined, and both might be associated with subacute inflammation, we took a transgenic approa...

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.

The E23K polymorphism of the pancreatic ␤-cell ATPsensitive K ؉ (K ATP ) channel subunit Kir6.2 (KCNJ11) is associated with type 2 diabetes in whites, and a recent in vitro study of the E23K variant suggests that the association to diabetes might be explained by a slight inhibition of serum insulin release. In a study comprising 519 unrelated glucose-tolerant subjects, we addressed the question as to whether the E23K variant was related to reduced serum insulin release during an oral glucose tolerance test (OGTT). Furthermore, the polymorphism was examined in a case-control study comprising 803 type 2 diabetic patients and 862 glucosetolerant control subjects. The E23K variant was associated with significant reductions in the insulinogenic index (P ‫؍‬ 0.022) and serum insulin levels under the response curve during an OGTT (0 -120 min) (P ‫؍‬ 0.014) as well as with an increase in BMI (P ‫؍‬ 0.013). In the present study, the association of the E23K polymorphism with type 2 diabetes was not significant (P ‫؍‬ 0.26). However, the K23K genotype significantly associated with type 2 diabetes in a meta-analysis of white case and control subjects (n ‫؍‬ 2,824, odds ratio [OR] 1.49, P ‫؍‬ 0.00022). In conclusion, the widespread E23K polymorphism may have a diabetogenic effect by impairing glucose-induced insulin release and increasing BMI.