Obrosova Irina G, Ilnytska Olga, Lyzogubov Valeriy V, Pavlov Ivan A, Mashtalir Nazar, Nadler Jerry L, Drel Viktor R
Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., Baton Rouge, LA 70808, USA.
Diabetes. 2007 Oct;56(10):2598-608. doi: 10.2337/db06-1176. Epub 2007 Jul 12.
Subjects with dietary obesity and pre-diabetes have an increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal models of this type of neuropathy have not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed a high-fat diet (HFD), a model of pre-diabetes and alimentary obesity.
Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks.
HFD-fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They also had motor and sensory nerve conduction deficits, tactile allodynia, and thermal hypoalgesia in the absence of intraepidermal nerve fiber loss or axonal atrophy. Despite the absence of overt hyperglycemia, the mice displayed augmented sorbitol pathway activity in the peripheral nerve, as well as 4-hydroxynonenal adduct nitrotyrosine and poly(ADP-ribose) accumulation and 12/15-lipoxygenase overexpression in peripheral nerve and dorsal root ganglion neurons. A 6-week feeding with normal chow after 16 weeks on HFD alleviated tactile allodynia and essentially corrected thermal hypoalgesia and sensory nerve conduction deficit without affecting motor nerve conduction slowing. Normal chow containing the aldose reductase inhibitor fidarestat (16 mg x kg(-1) x day (-1)) corrected all functional changes of HFD-induced neuropathy.
Similar to human subjects with pre-diabetes and obesity, HFD-fed mice develop peripheral nerve functional, but not structural, abnormalities and, therefore, are a suitable model for evaluating dietary and pharmacological approaches to halt progression and reverse diabetic neuropathy at the earliest stage of the disease.
患有饮食性肥胖和糖尿病前期的受试者发生神经传导减慢和小感觉纤维神经病变的风险增加。尚未描述这种类型神经病变的动物模型。本研究评估了高脂饮食（HFD）喂养的小鼠（一种糖尿病前期和饮食性肥胖模型）的神经病变变化及其对饮食和药物干预的敏感性。
雌性C57BL6/J小鼠喂食正常饮食或高脂饮食16周。
高脂饮食喂养的小鼠出现肥胖、血浆游离脂肪酸和胰岛素浓度升高以及糖耐量受损。它们还存在运动和感觉神经传导缺陷、触觉异常性疼痛和热痛觉减退，而无表皮内神经纤维丢失或轴突萎缩。尽管没有明显的高血糖，但小鼠外周神经中糖醇途径活性增强，同时外周神经和背根神经节神经元中4-羟基壬烯醛加合物硝基酪氨酸和聚（ADP-核糖）积累以及12/15-脂氧合酶过表达。在高脂饮食16周后用正常食物喂养6周可减轻触觉异常性疼痛，并基本纠正热痛觉减退和感觉神经传导缺陷，而不影响运动神经传导减慢。含有醛糖还原酶抑制剂非达司他（16mg·kg⁻¹·天⁻¹）的正常食物可纠正高脂饮食诱导的神经病变的所有功能变化。
与患有糖尿病前期和肥胖的人类受试者相似，高脂饮食喂养的小鼠出现外周神经功能异常，但无结构异常，因此是评估饮食和药物方法以在疾病最早阶段阻止进展和逆转糖尿病神经病变的合适模型。
