Lipids: A Suitable Therapeutic Target in Diabetic Neuropathy?
Lipids: A Suitable Therapeutic Target in Diabetic Neuropathy?
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脂质：糖尿病神经病中合适的治疗靶点？
DOI：
10.1155/2017/6943851
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发表时间：
2017
影响因子：
4.3
通讯作者：
Mendivil CO
中科院分区：
文献类型：
--
作者：
Perez-Matos MC;Morales-Alvarez MC;Mendivil CO
糖尿病性多发性神经病（DPN）包括具有共同发病机制的多种综合征。糖基化控制与DPN的相关性有限，支持其他因素的主要参与，其中之一是脂质和脂蛋白代谢的改变。血浆甘油三酯/残余脂蛋白与DPN风险之间存在一致的相关性。在培养的神经组织或糖尿病小鼠模型中的研究揭示了脂质代谢与DPN的联系机制。缺乏胰岛素作用会增加脂肪酸流向神经细胞，诱导线粒体功能障碍、异常蛋白激酶C信号传导和质膜理化性质的扰动。氧化的低密度脂蛋白与细胞受体结合，促进活性氧的产生，恶化线粒体功能，改变神经元的电特性。在动物模型中，补充特定脂肪酸可预防或逆转不同形式的DPN。对临床试验的事后和次要分析发现，降低胆固醇（他汀类药物和依折麦布）、降低胆固醇（贝特类药物）或脂质抗氧化剂（硫辛酸）治疗对DPN的进展和严重程度具有获益。然而，这些发现大多是假设产生的。随机试验是必要的，其中强化血脂正常化对DPN结果的影响进行了专门评估。
Diabetic polyneuropathy (DPN) encompasses multiple syndromes with a common pathogenesis. Glycemic control shows a limited correlation with DPN, arguing in favor of major involvement of other factors, one of which is alterations of lipid and lipoprotein metabolism. Consistent associations have been found between plasma triglycerides/remnant lipoproteins and the risk of DPN. Studies in cultured nerve tissue or in murine models of diabetes have unveiled mechanisms linking lipid metabolism to DPN. Deficient insulin action increases fatty acids flux to nerve cells, inducing mitochondrial dysfunction, anomalous protein kinase C signaling, and perturbations in the physicochemical properties of the plasma membrane. Oxidized low-density lipoproteins bind to cellular receptors and promote generation of reactive oxygen species, worsening mitochondrial function and altering the electrical properties of neurons. Supplementation with specific fatty acids has led to prevention or reversal of different modalities of DPN in animal models. Post hoc and secondary analyses of clinical trials have found benefits of cholesterol reducing (statins and ezetimibe), triglyceride-reducing (fibrates), or lipid antioxidant (thioctic acid) therapies over the progression and severity of DPN. However, these findings are mostly hypothesis-generating. Randomized trials are warranted in which the impact of intensive plasma lipids normalization on DPN outcomes is specifically evaluated.