Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance
Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance
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DOI：
10.1038/sj.ijo.0802501
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发表时间：
2003-12-01
影响因子：
4.9
通讯作者：
Yuan, M
中科院分区：
文献类型：
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作者：
Shoelson, SE;Lee, J;Yuan, M
与水杨酸酯相关的抗糖尿病作用已被发现多年，尽管其潜在的机制尚不清楚。鉴于最近在信号转导和胰岛素抵抗领域的发现，我们一直在重新研究这些影响。我们的研究结果表明，导致ikkβ激酶β (ikkβ)和NF-kappaB的信号通路在肥胖和高脂肪喂养动物的胰岛素反应组织中被激活。由于激活与胰岛素抵抗的发展相关，我们想知道通过这个信号是否可能参与胰岛素抵抗的发病机制。杂合基因缺失（Ikkbeta+/-）或水杨酸盐作为Ikkbeta抑制剂，改善胰岛素抵抗啮齿动物模型的胰岛素敏感性。此外，高剂量的水杨酸（阿司匹林或水杨酸）可改善II型糖尿病患者的胰岛素敏感性。我们的研究暗示了肥胖和II型糖尿病胰岛素抵抗的发病机制中的炎症过程，并确定了IKKbeta/ NF-kappaB通路是胰岛素抵抗的分子介质和胰岛素致敏的药理学靶点。
Antidiabetic effects associated with salicylates have been known for years, although the underlying mechanisms were not understood. We have been reinvestigating these effects in the light of recent discoveries in the areas of signal transduction and insulin resistance. Our findings showed that signaling pathways leading to IkappaB kinase beta (IKKbeta) and NF-kappaB are activated in insulin-responsive tissues of obese and high-fat-fed animals. Since activation correlates with the development of insulin resistance, we asked whether signaling through this might be involved in the pathogenesis of insulin resistance. Heterozygous gene deletion (Ikkbeta+/-) or salicylates, working as IKKbeta inhibitors, improved insulin sensitivity in insulin-resistant rodent models. Furthermore, high doses of salicylates ( aspirin or salicylate) improved insulin sensitivity in patients with type II diabetes. Our studies implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus and identify the IKKbeta/ NF-kappaB pathway as a molecular mediator of insulin resistance and pharmacological target for insulin sensitization.