Adenovirus infection results in alterations of insulin signaling and glucose homeostasis
Adenovirus infection results in alterations of insulin signaling and glucose homeostasis
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DOI：
10.1152/ajpendo.00723.2009
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发表时间：
2010-06-01
影响因子：
5.1
通讯作者：
Messina, Joseph L.
中科院分区：
文献类型：
--
作者：
Jiang, Shaoning;Gavrikova, Tatyana A.;Messina, Joseph L.
Jiang S，Gavrikova TA，Pereboev A，Messina JL.腺病毒感染导致胰岛素信号传导和葡萄糖稳态的改变。美国生理学杂志内分泌代谢298：E1295-E1304，2010年。首次发表于2010年4月13日; doi：10.1152/ajpendo.00723.2009.-重组腺病毒（Ad）载体可引发炎症反应，限制了其在基因治疗和基础研究中的应用。尽管越来越多的努力，以更好地了解广告感染，很少有人知道它如何影响细胞代谢反应。在目前的研究中，我们探讨了Ad载体对胰岛素信号分子和葡萄糖稳态的影响。将非复制型Ad载体通过尾静脉注射到大鼠中，并在注射后4-13天检查胰岛素信号传导和葡萄糖耐量。Ad载体感染显著降低了大鼠肝脏中胰岛素受体（IR）和胰岛素受体底物1和2（IRS-1，IRS-2）的总水平，导致IR，IRS-1和IRS-2的胰岛素诱导酪氨酸磷酸化降低，IRS-1和IRS-2与磷酸肌醇3-激酶（PI 3 K）的相互作用降低。此外，Ad感染导致全身葡萄糖稳态受损，在IR、IRS-1和IRS-2的蛋白水平开始正常化后13天恢复。TNF抑制剂的表达或库普弗细胞的消耗减弱了Ad载体诱导的胰岛素信号分子的减少，表明库普弗细胞活化在这一过程中的潜在作用。这些研究提供了证据表明，Ad载体的全身施用可损害肝脏中的胰岛素信号传导，导致全身葡萄糖代谢改变。因此，当Ad载体用于研究或基因治疗时，需要考虑Ad载体感染对胰岛素作用和葡萄糖代谢的影响，并且可能更广泛地适用于其他病毒制剂。
Jiang S, Gavrikova TA, Pereboev A, Messina JL. Adenovirus infection results in alterations of insulin signaling and glucose homeostasis. Am J Physiol Endocrinol Metab 298: E1295-E1304, 2010. First published April 13, 2010; doi:10.1152/ajpendo.00723.2009.-Recombinant adenovirus (Ad) vectors can initiate an inflammatory response, limiting its use in gene therapy and basic research. Despite increased efforts to better understand Ad infection, little is known about how it affects cellular metabolic responses. In the current studies, we explored the effects of Ad vectors on insulin signaling molecules and glucose homeostasis. Nonreplicative Ad vectors were injected into rats through the tail vein, and at 4-13 days postinjection insulin signaling and glucose tolerance were examined. Ad vector infection significantly reduced total levels of the insulin receptor (IR), and insulin receptor substrates 1 and 2 (IRS-1, IRS-2) in the liver of rats, resulting in decreased insulin-induced tyrosine phosphorylation of IR, IRS-1, and IRS-2, and decreased interaction of IRS-1 and IRS-2 with phosphoinositide 3-kinase (PI3K). In addition, Ad infection resulted in impaired systemic glucose homeostasis, which recovered by 13 days, after the protein levels of IR, IRS-1, and IRS-2 had started to normalize. Expression of a TNF inhibitor or Kupffer cell depletion attenuated the Ad vector-induced decreases of insulin signaling molecules, indicating a potential role of Kupffer cell activation in this process. These studies provide evidence that systemic administration of Ad vectors can impair insulin signaling in liver, resulting in altered systemic glucose metabolism. Thus, effects of Ad vector infection on insulin action and glucose metabolism need to be considered when Ad vectors are used in research or gene therapy and may be more broadly applicable to other viral agents.