High-fat diet-induced neuropathy of pre-diabetes and obesity - Effects of "healthy" diet and aldose reductase inhibition
High-fat diet-induced neuropathy of pre-diabetes and obesity - Effects of "healthy" diet and aldose reductase inhibition
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DOI：
10.2337/db06-1176
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发表时间：
2007-10-01
期刊：
影响因子：
7.7
通讯作者：
Drel, Viktor R.
中科院分区：
文献类型：
--
作者：
Obrosova, Irina G.;Ilnytska, Olga;Drel, Viktor R.
目的：饮食肥胖和糖尿病前期的受试者发生神经传导减慢和小感觉神经病的风险增加。这种类型的神经病的动物模型还没有被描述。这项研究评估了高脂饮食(HFD)小鼠的神经病变及其对饮食和药物干预的适应性。高脂饮食(HFD)是糖尿病前期和消化性肥胖的模型。研究设计和方法：雌性C57BL6/J小鼠喂饲正常饮食或高脂饮食16周。结果高脂饮食小鼠出现肥胖，血浆FFA和胰岛素浓度增加，糖耐量受损。他们也有运动神经和感觉神经传导缺陷，触觉过敏，以及没有表皮内神经纤维丢失或轴突萎缩的热痛觉减退。尽管没有明显的高血糖，但小鼠外周神经中山梨醇途径活性增强，周围神经和背根神经节神经元中4-羟基壬醛加合物硝基酪氨酸和聚(ADP-核糖)积聚，12/15-脂氧合酶过度表达。高脂饮食16周后，正常饲料喂养6周，可减轻触觉痛觉异常，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。正常饲料中含有醛糖还原酶抑制剂fidarestat(16 mg中心点kg(-1)中心点日(-1))，可纠正HFD所致神经病变的所有功能改变。结论：与糖尿病前期和肥胖的人类受试者相似，喂饲HFD的小鼠出现周围神经功能异常，但不出现结构性异常，因此是在疾病早期评估阻止进展和逆转糖尿病神经病变的饮食和药物方法的合适模型。
OBJECTIVE-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.RESEARCH DESIGN AND METHODS-Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks.RESULTS-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 center dot kg(-1) center dot day(-1)) corrected all functional changes of HFD-induced neuropathy.CONCLUSIONS-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.