Direct insulin signaling of neurons reverses diabetic neuropathy
Direct insulin signaling of neurons reverses diabetic neuropathy
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DOI：
10.2337/diabetes.53.7.1824
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发表时间：
2004-07-01
期刊：
影响因子：
7.7
通讯作者：
Zochodne, DW
中科院分区：
文献类型：
--
作者：
Brussee, V;Cunningham, FA;Zochodne, DW
糖尿病性多发性神经病是最常见的获得性弥漫性周围神经系统疾病。一般认为胰岛素通过降低葡萄糖水平间接有益于人类和实验性糖尿病神经病变。胰岛素还提供了对神经元和轴突的有力的直接支持，并且外周神经元上的直接胰岛素信号传导的异常可能与这种疾病的发展有关。在这里，我们报告，直接神经元（鞘内）输送低剂量的胰岛素（0.1-0.2 IU，每天），不足以减少胰岛素或等摩尔IGF-I，但不是鞘内生理盐水或皮下胰岛素，改善和逆转运动和感觉传导速度减慢的糖尿病大鼠使用链脲佐菌素。此外，胰岛素和IGF-I同样逆转腓肠神经中有髓感觉轴突的萎缩。通过观察鞘内注射异硫氰酸荧光素标记的胰岛素进入并标记单个腰脊神经节神经元，证实了鞘内注射胰岛素具有向感觉神经元发出信号的能力。此外，我们证实，这种神经元表达胰岛素受体，如以前所建议的Sugimoto等。最后，我们隔离鞘内胰岛素在非糖尿病大鼠使用抗胰岛素抗体。传导减慢和轴突萎缩类似糖尿病的变化产生的抗胰岛素，但不是由抗大鼠白蛋白抗体输注。通过包括脑脊液在内的途径在外周神经元上的胰岛素直接信号传导缺陷可能与糖尿病周围神经病变的发展有关。
Diabetic polyneuropathy is the most common acquired diffuse disorder of the peripheral nervous system. It is generally assumed that insulin benefits human and experimental diabetic neuropathy indirectly by lowering glucose levels. Insulin also provides potent direct support of neurons and axons, and there is a possibility that abnormalities in direct insulin signaling on peripheral neurons relate to the development of this disorder. Here we report that direct neuronal (intrathecal) delivery of low doses of insulin (0.1-0.2 IU daily), insufficient to reduce glycemia or equimolar IGF-I but not intrathecal saline or subcutaneous insulin, improved and reversed slowing of motor and sensory conduction velocity in rats rendered diabetic using streptozotocin. Moreover, insulin and IGF-I similarly reversed atrophy in myelinated sensory axons in the sural nerve. That intrathecal insulin had the capability of signaling sensory neurons was confirmed toy observing that fluorescein isothiocyanate-labeled insulin given intrathecally accessed and labeled individual lumbar dorsal root ganglion neurons. Moreover, we confirmed that such neurons express the insulin receptor, as previously suggested by Sugimoto et al. Finally, we sequestered intrathecal insulin in nondiabetic rats using an anti-insulin antibody. Conduction slowing and axonal atrophy resembling the changes in diabetes were generated by anti-insulin but not by an anti-rat albumin antibody infusion. Defective direct signaling of insulin on peripheral neurons through routes that include the cerebrospinal fluid may relate to the development of diabetic peripheral neuropathy.