Although diabetic mice have been studied for decades, little is known about the cell type specific contributions to diabetic neuropathy (DN). Schwann cells (SCs) myelinate and provide trophic support to peripheral nervous system axons. Altered SC metabolism leads to myelin defects, which can be seen both in inherited and DNs. How SC metabolism is altered in DN is not fully understood, but it is clear that insulin resistance underlies impaired lipid metabolism in many cell types throughout the body via the phosphoinositide 3-kinase/protein kinase b (PKB)/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Here, we created an insulin resistant SC by deleting both insulin receptor (INSR) and insulin-like growth factor receptor 1 (IGF1R), to determine the role of this signaling pathway in development and response to injury in order to understand SC defects in DN. We found that myelin is thinner throughout development and adulthood in INSR/IGF1R Schwann cell specific knock out mice. The nerves of these mutant mice had reduced expression of key genes that mediate fatty acid and cholesterol synthesis due to reduced mTOR-sterol regulatory element-binding protein signaling. In adulthood, these mice show sensory neuropathy phenotypes reminiscent of diabetic mice. Altogether, these data suggest that SCs may play an important role in DN and targeting their metabolism could lead to new therapies for DN.

中文翻译：

---

雪旺细胞中破坏胰岛素信号传导会破坏髓鞘形成，并引起感觉神经病。

尽管已经对糖尿病小鼠进行了数十年的研究，但关于细胞类型对糖尿病性神经病（DN）的特定贡献知之甚少。雪旺氏细胞（SCs）发生髓鞘形成并向周围神经系统轴突提供营养支持。SC代谢改变会导致髓磷脂缺陷，这在遗传性和DN中均可见。尚不完全了解DN中SC代谢的变化方式，但是很明显，胰岛素抵抗是通过磷酸肌醇3-激酶/蛋白激酶b（PKB）/雷帕霉素哺乳动物靶点（PI3K）在体内许多细胞类型中损害脂质代谢的基础/ AKT / mTOR）途径。在这里，我们通过删除胰岛素受体（INSR）和胰岛素样生长因子受体1（IGF1R）来创建胰岛素抵抗性SC，为了确定该信号通路在发育和对损伤的反应中的作用，以了解DN中的SC缺陷。我们发现，在INSR / IGF1R Schwann细胞特异性敲除小鼠中，髓磷脂在整个发育过程中和成年期都较薄。这些突变小鼠的神经由于mTOR-固醇调节元件结合蛋白信号传导的减少而介导了脂肪酸和胆固醇合成的关键基因的表达减少。在成年期，这些小鼠表现出让人联想到糖尿病小鼠的感觉神经病表型。总而言之，这些数据表明SC可能在DN中起重要作用，靶向其新陈代谢可能导致DN的新疗法。这些突变小鼠的神经由于mTOR-固醇调节元件结合蛋白信号传导的减少而介导了脂肪酸和胆固醇合成的关键基因的表达减少。在成年期，这些小鼠表现出感觉神经病的表型，使人联想到糖尿病小鼠。总而言之，这些数据表明SC可能在DN中起重要作用，靶向其新陈代谢可能导致DN的新疗法。这些突变小鼠的神经由于mTOR-固醇调节元件结合蛋白信号传导的减少而介导了脂肪酸和胆固醇合成的关键基因的表达减少。在成年期，这些小鼠表现出感觉神经病的表型，使人联想到糖尿病小鼠。总而言之，这些数据表明SC可能在DN中起重要作用，靶向其新陈代谢可能导致DN的新疗法。