Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance.-猫眼课题宝

DOI：

10.1186/s12933-015-0223-2

发表时间：

2015-05-20

期刊：

Cardiovascular diabetology

影响因子：

9.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

House LM 2nd;Morris RT;Barnes TM;Lantier L;Cyphert TJ;McGuinness OP;Otero YF

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484635/?report=classic

内毒素(即内毒素)可诱导强烈的炎症反应，并伴有心血管功能障碍和胰岛素抵抗。一氧化氮(NO)过多导致血管功能障碍。然而，炎症本身也会导致骨骼肌中的胰岛素抵抗。我们试图调查在没有炎症应激的情况下，由于NO供应增加而导致的心血管功能障碍是否可以促进胰岛素抵抗。此外，我们还研究了诱导型一氧化氮合酶(iNOS或NOS2)在调节内毒素诱导的胰岛素刺激的肌肉葡萄糖摄取(MGU)减少中的作用。NO供体输注对胰岛素刺激的全身和肌肉葡萄糖摄取(高胰岛素-正常血糖钳)以及心血管系统的影响在长期导管化的野生型(WT)小鼠中进行了评估。在WT和全局iNOS基因敲除(KO)小鼠中，评估了内毒素对胰岛素作用和心血管系统的影响。分别用微球和超声心动图评价组织血流量和心功能。同时检测胰岛素信号活性和促炎标志物的基因表达。在骨骼肌血流无变化的情况下，不输注供体可降低平均动脉压、全身葡萄糖需要量和MGU。脂多糖可降低WT小鼠的平均动脉压和血糖需求，但不能降低iNOS KO小鼠的平均动脉压和血糖需求。最后，尽管有完整的炎症反应，iNOS KO小鼠仍免受内毒素介导的心输出量减少的影响。无论是否存在iNOS，脂多糖均可损伤体内的MGU。然而，在体外，从内毒素处理的iNOS KO动物获得的肌肉中的胰岛素作用受到保护。一氧化氮过量和内毒素通过减少MGU而损害血糖控制。脂多糖通过炎症对心肌细胞的直接影响以及通过间接的NO驱动的心血管功能障碍来损害MGU。本文的在线版本(doi：10.1186/s12933-0150223-2)包含补充材料，授权用户可以使用。

Endotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction. However, inflammation itself also induces insulin resistance in skeletal muscle. We sought to investigate whether the cardiovascular dysfunction induced by increased NO availability without inflammatory stress can promote insulin resistance. Additionally, we examined the role of inducible nitric oxide synthase (iNOS or NOS2), the source of the increase in NO availability, in modulating LPS-induced decrease in insulin-stimulated muscle glucose uptake (MGU). The impact of NO donor infusion on insulin-stimulated whole-body and muscle glucose uptake (hyperinsulinemic-euglycemic clamps), and the cardiovascular system was assessed in chronically catheterized, conscious mice wild-type (WT) mice. The impact of LPS on insulin action and the cardiovascular system were assessed in WT and global iNOS knockout (KO) mice. Tissue blood flow and cardiac function were assessed using microspheres and echocardiography, respectively. Insulin signaling activity, and gene expression of pro-inflammatory markers were also measured. NO donor infusion decreased mean arterial blood pressure, whole-body glucose requirements, and MGU in the absence of changes in skeletal muscle blood flow. LPS lowered mean arterial blood pressure and glucose requirements in WT mice, but not in iNOS KO mice. Lastly, despite an intact inflammatory response, iNOS KO mice were protected from LPS-mediated deficits in cardiac output. LPS impaired MGU in vivo, regardless of the presence of iNOS. However, ex vivo, insulin action in muscle obtained from LPS treated iNOS KO animals was protected. Nitric oxide excess and LPS impairs glycemic control by diminishing MGU. LPS impairs MGU by both the direct effect of inflammation on the myocyte, as well as by the indirect NO-driven cardiovascular dysfunction. The online version of this article (doi:10.1186/s12933-015-0223-2) contains supplementary material, which is available to authorized users.