Insulin down-regulates the inducible nitric oxide synthase pathway: nitric oxide as cause and effect of diabetes?
Insulin down-regulates the inducible nitric oxide synthase pathway: nitric oxide as cause and effect of diabetes?
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DOI：
10.4049/jimmunol.159.11.5329
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发表时间：
1997-12
影响因子：
4.4
通讯作者：
R. Stevens;D. Sutherland;J. Ansite;M. Saxena;T. Rossini;B. Levay-Young;B. Hering;C. Mills
中科院分区：
文献类型：
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作者：
R. Stevens;D. Sutherland;J. Ansite;M. Saxena;T. Rossini;B. Levay-Young;B. Hering;C. Mills
本文的证据表明，胰岛素可以下调体内诱导型一氧化氮合酶（iNOS）途径。iNOS通路在糖尿病易感大鼠和小鼠中上调，并与自身免疫过程相关。然而，这里提出的结果表明，巨噬细胞一氧化氮（NO）的生产和iNOS mRNA的表达也升高糖尿病的大鼠或小鼠链脲佐菌素注射，其中没有主要的自身免疫成分。胰岛素给药可减少自身免疫易感和链脲佐菌素诱导的糖尿病啮齿动物的NO产生最后，胰岛素降低正常宿主中巨噬细胞NO的产生。这些结果表明，自身免疫模式是不足以解释糖尿病中增加的NO。作为解释胰岛素介导的NO产生调节的潜在机制，TGF-1可能参与其中，因为1）糖尿病小鼠的巨噬细胞产生的TGF-β 1少于正常宿主的巨噬细胞; 2）糖尿病小鼠的循环TGF-β 1水平较低; 3）胰岛素给药增加正常小鼠的循环TGF-β 1。总之，这些结果提供了证据，表明糖尿病中NO的增加不仅是β细胞破坏的原因，而且是β细胞破坏的影响，部分原因是迄今为止未被认识到的胰岛素免疫调节活性。
Evidence in this paper indicates that insulin can down-regulate the inducible nitric oxide synthase (iNOS) pathway in vivo. The iNOS pathway is up-regulated in diabetes-prone rats and mice and is associated with an autoimmune process. However, the results presented here indicate that macrophage nitric oxide (NO) production and iNOS mRNA expression are also elevated in rats or mice made diabetic by streptozotocin injection in which there is no primary autoimmune component. Insulin administration reduces NO production in autoimmune-prone and streptozotocin-induced diabetic rodents. Finally, insulin decreases macrophage NO production in normal hosts. These results indicate that the autoimmune paradigm is inadequate to explain increased NO in diabetes. As a potential mechanism to explain insulin-mediated regulation of NO production, TGF-1 may be involved because 1) macrophages from diabetic mice produce less TGF-beta1 than macrophages from normal hosts; 2) the circulating TGF-beta1 level is lower in diabetic mice; and 3) insulin administration increases circulating TGF-beta1 in normal mice. Together, these results provide evidence that increased NO in diabetes is not only a cause but also an effect of beta-cell destruction and results in part from a heretofore unrecognized immunomodulatory activity of insulin.