Department of Medical Chemistry, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.
Central Research Laboratory, Kansai Medical University, Hirakata, Japan.
Eur J Neurosci. 2018 Jan;47(2):126-139. doi: 10.1111/ejn.13771. Epub 2018 Jan 11.
Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy.
周围神经病变是 2 型糖尿病最常见和最严重的并发症之一。糖尿病周围神经病变的特征是远端对称性感觉运动多发性神经病，其发病率在 40 岁或以上的患者中增加。尽管数十年来进行了广泛的研究，但除了控制血糖和改善生活方式外，对于糖尿病周围神经病变几乎没有有效的治疗方法。糖尿病周围神经病变最早的变化发生在感觉神经纤维中，最初的变性和再生导致疼痛。为了寻求有效的治疗方法，我们在这里通过给小鼠注射 2 次链脲佐菌素和烟酰胺来制备 2 型糖尿病小鼠模型，并使用我们之前建立的坐骨神经横断-再生模型来检查神经再生的能力。最后一次注射后 17 周，小鼠出现 2 型糖尿病的症状，即葡萄糖耐量受损、胰岛素水平降低、机械性痛觉过敏和足底皮肤感觉神经纤维受损。与年轻健康小鼠相比，这些小鼠在轴突切断后 2 周表现出功能恢复和神经再生延迟，与年龄匹配的非糖尿病小鼠相比则延迟 1 周。此外，2 型糖尿病小鼠的 DRG 神经元中 PTEN 的表达增加。在神经切断部位给予 4 周的 PTEN 抑制剂可显著促进轴突运输和功能恢复。这项研究表明，2 型糖尿病模型的周围神经再生受损，与坐骨神经横断结合适合研究早期糖尿病周围神经病变的发病机制和治疗。
