Tumor necrosis factor-α induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation
Tumor necrosis factor-α induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation
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DOI：
10.2337/diabetes.54.10.2939
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发表时间：
2005-10-01
期刊：
影响因子：
7.7
通讯作者：
Pedersen, BK
中科院分区：
文献类型：
--
作者：
Plomgaard, P;Bouzakri, K;Pedersen, BK
大多数与生活方式有关的慢性病的特点是低度全身炎症和胰岛素抵抗。肿瘤坏死因子-α(TNF-α)浓度过高与胰岛素抵抗的发生有关，但在人类身上缺乏直接证据。在这里，我们证明了在健康人中输注肿瘤坏死因子-ot诱导了骨骼肌中的胰岛素抵抗，而不影响内源性葡萄糖的产生，这是通过血糖钳和稳定同位素示踪法相结合的方法估计的。肿瘤坏死因子-α通过改变胰岛素信号转导，直接损害葡萄糖的摄取和代谢。肿瘤坏死因子-α的输注增加了P76 S6的磷酸化。伴随着胰岛素受体底物-1丝氨酸增加和酪氨酸磷酸化减少，胰岛素受体底物-1的丝氨酸增加和酪氨酸磷酸化减少。这些信号效应与Akt底物160的磷酸化受损有关，Akt底物160是典型的胰岛素信号级联调控GLUT4易位和葡萄糖摄取的最近端步骤。因此，过量的肿瘤坏死因子-α对人体的胰岛素信号和全身葡萄糖摄取具有负面调节作用。OUT结果提供了低度系统性炎症和代谢综合征之间的分子联系。
Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation And insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-ot infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined englycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p76 S6. kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH2-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identifted in the canonical insulin signaling cascade regulating GLUT4 trairislocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Out results provide a molecular link between low-grade systentic inflammation and the metabolic syndrome.