Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade
Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade
复制标题
DOI：
10.1097/00003246-200104000-00032
复制
发表时间：
2001-04-01
影响因子：
8.8
通讯作者：
Smith, RJ
中科院分区：
文献类型：
--
作者：
McCowen, KC;Ling, PR;Smith, RJ
目的：确定持续3天内毒素输注对体内大鼠肝脏和骨骼肌中胰岛素信号传导途径早期步骤的影响;在已建立的胰岛素抵抗急性内毒素模型中检查胰岛素信号传导。设计：前瞻性对照动物研究。设置：大学研究实验室。受试者：雄性Sprague-Dawley大鼠：3天内毒素研究中24例，各急性内毒素研究中22例。干预：在长期内毒素血症研究中，mg.kg通过颈静脉导管给予内毒素（1 www.example.com（-1. 24 hrs（-1））74小时，然后注射胰岛素，在急性内毒素血症研究中，施用内毒素推注（1 mg/kg），并在4小时后研究胰岛素信号传导应答。在持续性内毒素血症大鼠的肝脏中，胰岛素刺激的胰岛素受体酪氨酸磷酸化显著降低（74%），胰岛素受体底物（IRS）-1（74%）和IRS 2（53%）;磷脂酰肌醇3-激酶的p85亚基与IRS 1的结合（80%）;和IRS 1可沉淀的磷脂酰肌醇3-激酶活性（>90%）。这些发现与胰岛素受体（37%）、IRS 1（60%）和IRS 2（23%）丰度的显著降低相关。骨骼肌中的信号传导也受到类似的影响，IRS 1磷酸化（49%）、IRS 1丰度（50%）和p85与IRS 1的结合（57%）减少。胰岛素信号传导4小时内毒素管理后没有不同的controls.Conclusions：长期的内毒素血症与胰岛素信号传导途径的早期步骤，这至少部分地解释了胰岛素受体和IRS蛋白的丰度减少显着的赤字。在足够营养的条件下，内毒素给药后4小时，信号传导缺陷不明显，表明胰岛素抵抗逐渐发展，可能需要伴随营养不良，并且不被内毒素耐受性的发展逆转。
Objectives: To determine the effects of sustained, 3-day endotoxin infusion on early steps of the insulin-signaling pathway in rat liver and skeletal muscle in vivo; to examine insulin signaling in well-established acute endotoxin models of insulin resistance.Design: Prospective, controlled animal study.Setting: University research laboratory.Subjects: Male Sprague-Dawley rats: 24 in the 3-day endotoxin study, 22 in each acute endotoxin study,Interventions: In prolonged endotoxemia studies, endotoxin (1 mg.kg(-1).24 hrs(-1)) was administered via jugular venous catheter for 74 hrs, Insulin was then injected, and liver and skeletal muscle were removed after 5 mins, In acute endotoxemia studies, an endotoxin bolus (1 mg/kg) was administered, and insulin-signaling responses were studied after 4 hrs,Measurements and Main Results:ln liver of rats with sustained endotoxemia, there were significant decreases in insulin-stimulated tyrosine phosphorylation of insulin receptors (74%), insulin receptor substrate (IRS)-1 (74%), and IRS2 (53%); binding of the p85 subunit of phosphatidylinositide 3-kinase to IRS1 (80%); and IRS1-precipitable phosphatidylinositide 3-kinase activity (>90%). These findings were associated with significant reductions in abundance of insulin receptors (37%), IRS1 (60%), and IRS2 (23%). Signaling in skeletal muscle was similarly affected, with reduced IRS1 phosphorylation (49%), IRS1 abundance (50%), and binding of p85 to IRS1 (57%). Insulin signaling 4 hrs after endotoxin administration was not different from controls.Conclusions: Prolonged endotoxemia is associated with marked deficits in early steps of the insulin-signaling pathway, which are at least partly explained by reduced abundance of the insulin receptor and IRS proteins. Signaling defects were not evident 4 hrs after endotoxin administration under conditions of adequate nutrition, indicating that insulin resistance develops gradually, may require concomitant malnutrition, and is not reversed by the development of endotoxin tolerance.