Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
The Genome Editing and Viral Vector Cores, University of Iowa, Iowa City, IA 52242, USA.
J Diabetes Res. 2021 Mar 15;2021:5564477. doi: 10.1155/2021/5564477. eCollection 2021.
To rigorously explore the role of omega-3 polyunsaturated fatty acids (PUFA) in the treatment of diabetic peripheral neuropathy (DPN), we have created a transgenic mouse utilizing a Cre-lox promoter to control overexpression of human 15-lipoxygenase-1 (15-LOX-1). In this study, we sought to determine the effect of treating type 2 diabetic wild-type mice and transgenic mice ubiquitously overexpressing 15-LOX-1 with menhaden oil on endpoints related to DPN. Wild-type and transgenic mice on a C57Bl/6J background were divided into three groups. Two of each of these groups were used to create a high-fat diet/streptozotocin model for type 2 diabetes. The remaining mice were control groups. Four weeks later, one set of diabetic mice from each group was treated with menhaden oil for twelve weeks and then evaluated using DPN-related endpoints. Studies were also performed using dorsal root ganglion neurons isolated from wild-type and transgenic mice. Wild-type and transgenic diabetic mice developed DPN as determined by slowing of nerve conduction velocity, decreased sensory nerve fibers in the skin and cornea, and impairment of thermal and mechanical sensitivity of the hindpaw compared to their respective control mice. Although not significant, there was a trend for the severity of these DPN-related deficits to be less in the diabetic transgenic mice compared to the diabetic wild-type mice. Treating diabetic wild-type and transgenic mice with menhaden oil improved the DPN-related endpoints with a trend for greater improvement or protection by menhaden oil observed in the diabetic transgenic mice. Treating dorsal root ganglion neurons with docosahexanoic acid but not eicosapentaenoic acid significantly increased neurite outgrowth with greater efficacy observed with neurons isolated from transgenic mice. Targeting pathways that will increase the production of the anti-inflammatory metabolites of omega-3 PUFA may be an efficacious approach to developing an effective treatment for DPN.
为了严格探索ω-3 多不饱和脂肪酸（PUFA）在治疗糖尿病周围神经病变（DPN）中的作用，我们利用 Cre-lox 启动子创建了一种转基因小鼠，以控制人 15-脂氧合酶-1（15-LOX-1）的过表达。在这项研究中，我们试图确定用鲱鱼油治疗 2 型糖尿病野生型小鼠和广泛过表达 15-LOX-1 的转基因小鼠对与 DPN 相关的终点的影响。具有 C57Bl/6J 背景的野生型和转基因小鼠分为三组。每组中的两种用于创建 2 型糖尿病高脂肪饮食/链脲佐菌素模型。其余的小鼠为对照组。四周后，从每组中的一组糖尿病小鼠开始用鲱鱼油治疗 12 周，然后用 DPN 相关终点进行评估。还使用从野生型和转基因小鼠分离的背根神经节神经元进行了研究。与各自的对照小鼠相比，神经传导速度减慢、皮肤和角膜感觉神经纤维减少以及后爪热和机械敏感性受损，表明野生型和转基因糖尿病小鼠出现 DPN。尽管没有统计学意义，但与野生型糖尿病小鼠相比，糖尿病转基因小鼠这些 DPN 相关缺陷的严重程度有减轻的趋势。用鲱鱼油治疗糖尿病野生型和转基因小鼠可改善 DPN 相关终点，并且在糖尿病转基因小鼠中观察到鲱鱼油的改善或保护作用呈趋势。用二十二碳六烯酸处理背根神经节神经元而不是二十碳五烯酸可显著增加神经突生长，并且从转基因小鼠分离的神经元观察到更大的功效。针对可增加 ω-3 PUFA 的抗炎代谢物产量的途径可能是开发 DPN 有效治疗方法的有效方法。
