TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS SIGNALING FROM THE INSULIN-RECEPTOR
TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS SIGNALING FROM THE INSULIN-RECEPTOR
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DOI：
10.1073/pnas.91.11.4854
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发表时间：
1994-05-24
影响因子：
11.1
通讯作者：
SPIEGELMAN, BM
中科院分区：
文献类型：
--
作者：
HOTAMISLIGIL, GS;MURRAY, DL;SPIEGELMAN, BM
胰岛素抵抗是与感染和癌症相关的常见问题，最重要的是，它是非胰岛素依赖型糖尿病的核心组成部分。我们最近发现，肿瘤坏死因子（TNF）α 是非胰岛素依赖型糖尿病动物模型中胰岛素抵抗的关键介质。在这里，我们研究 TNF-α 如何干扰胰岛素作用。脂肪细胞长期暴露于低浓度的 TNF-α 会强烈抑制胰岛素刺激的葡萄糖摄取。同时，TNF-α治疗导致胰岛素刺激的胰岛素受体(IR)自身磷酸化适度降低，并且IR底物1（体内IR的主要底物）的磷酸化显着降低。从 TNF-α 处理的细胞中分离出的 IR 在体外自磷酸化和磷酸化 IR 底物 1 的能力方面也存在缺陷。这些结果表明，TNF-α 通过其受体直接干扰胰岛素信号传导，从而阻断胰岛素的生物作用。
Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.