Effect of exogenous fatty acids on diabetes neural/neurovascular complications

 描述（由申请人提供）：良好的血糖控制是糖尿病周围神经病变（DPN）唯一公认的治疗方法，但研究表明它只能减缓进展。因此，除了高血糖之外，其他因素也会导致DPN，因此需要更好地了解这些因素，以发现有效的治疗方法。在拟议的研究中，我们将检验不同脂肪酸类别对DPN有负面、中性或正面影响的假设。脂质已被证明是疾病的主要危险因素，但还没有全面分析不同类别的脂肪酸对DPN的影响。我们将使用新型2型糖尿病啮齿动物模型并操纵饮食，以增加循环和组织中单不饱和脂肪酸（MUFA）和多不饱和脂肪酸（PUFA）的水平。具体而言，我们将检查富含油酸（18：1，MUFA）、亚油酸（18：2，n-6 PUFA）、γ-亚麻酸（18：3，n-6 PUFA）、α-亚麻酸（18：3，n-3 PUFA）或二十碳五烯酸（20：5，EPA，n-3 PUFA）和二十二碳六烯酸（22：6，DHA，n-3 PUFA）的膳食对DPN和神经血管功能的潜在负面、中性或正面益处。DPN终点将包括确定运动和感觉神经传导速度以及皮肤和角膜中小感觉神经的密度和功能变化。后一个终点将使我们能够检查脂肪酸饮食的影响， 神经损伤或修复的变化。预计在糖尿病啮齿动物的饮食中补充富含油酸（橄榄油）或亚油酸（红花油）的油不会产生什么有益效果，甚至可能加剧DPN和神经血管功能障碍。补充γ-亚麻酸（月见草报春花油）或α-亚麻酸（亚麻籽油）的饮食预计是有益的，但程度低于补充EPA和DHA的饮食，EPA和DHA来自鲱鱼（鱼）油。我们建议增加饮食中n-3 PUFA（来自亚麻籽油或鲱鱼油）而不是γ-亚麻酸（来自月见报春花油的n-6 PUFA）的水平将降低n-6与n-3脂肪酸的比例，这是炎症减少的标志。由于糖尿病患者α-亚麻酸转化为EPA的能力降低，我们预测增加膳食中EPA和DHA的水平而不是α-亚麻酸将导致消退素的产生增加。消退素由EPA和DHA通过15-脂氧合酶-1（15-LOX-1）产生，具有抗炎和神经保护特性。我们认为，EPA和DHA治疗患有2型糖尿病的啮齿动物将通过减少炎症应激、改善神经血管功能和介导神经修复对DPN产生最大影响。我们还提出，用水杨酰水杨酸（双水杨酯）治疗啮齿动物将增加15-LOX-1的组织表达，导致消退素的产生增加，并且当用双水杨酯和鲱鱼油组合治疗患有2型糖尿病的啮齿动物时，对DPN和神经血管并发症的疗效甚至更大。这些临床前研究将提供必要的信息，以证明鱼油和双水杨酸治疗DPN的临床试验的合理性。

 DESCRIPTION (provided by applicant): Good glycemic control is the only recognized treatment for diabetic peripheral neuropathy (DPN) but studies have shown that it only slows progression. Therefore, other factors besides hyperglycemia must contribute to DPN, and there is a need for a better understanding of what these factors are in order to discover effective treatments. In the proposed studies we will test the hypothesis that different fatty acid classes have either a negative, neutral or positive effect on DPN. Lipids have been shown to be a major risk factor for diseases but there has been no comprehensive analysis of the effect of different classes of fatty acids on DPN. We will use novel rodent models of type 2 diabetes and manipulate diets so as to increase circulating and tissue levels of monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids. Specifically we will examine the potential negative, neutral or positive benefits of dietary enrichment with oleic acid (18:1, MUFA), linoleic acid (18:2, n-6 PUFA), γ-linolenic acid (18:3, n-6 PUFA), α-linolenic acid (18:3, n-3 PUFA) or eicosapentaenoic acid (20:5, EPA, n-3 PUFA) and docosahexaenoic acid (22:6, DHA, n-3 PUFA) on DPN and neurovascular function. The DPN endpoints will include determination of motor and sensory nerve conduction velocity and changes in the density and function of small sensory nerves in the skin and cornea. The latter endpoints will allow us to examine the effect of fatty acid dietary changes on nerve damage or repair. It is expected that supplementing diets of diabetic rodents with oils enriched in oleic acid (olive oil) or linoleic acid (safflower oil) will have little beneicial effect or may even exacerbate DPN and neurovascular dysfunction. Diets supplemented with γ- linolenic acid (evening primrose oil) or α-linolenic acid (flaxseed oil) are expected to be beneficial but to a lesser extent than diets supplemented with EPA and DHA, to be derived from menhaden (fish) oil. We propose that increasing dietary levels of n-3 PUFA (derived from flaxseed oil or menhaden oil) but not γ- linolenic acid (n-6 PUFA derived from evening primrose oil) will lower the n-6 to n-3 fatty acid ratio, a marker for reduced inflammation. Due to reduced ability in diabetes of conversion of α-linolenic acid to EPA we predict that increasing dietary levels of EPA and DHA but not α-linolenic acid will lead to an increased production of resolvins. Resolvins are produced from EPA and DHA by 15-lipoxygenase-1 (15-LOX-1) and have anti-inflammatory and neuroprotective properties. We propose that EPA and DHA treatment of rodents with type 2 diabetes will have the greatest impact on DPN through reducing inflammatory stress, improving neurovascular function and mediating nerve repair. We also propose that treating rodents with salicylsalicylic acid (salsalate) will increase tissue expressio of 15-LOX-1 leading to increased production of resolvins and even greater efficacy toward DPN and neurovascular complications when rodents with type 2 diabetes are treated with the combination of salsalate and menhaden oil. These preclinical studies will provide needed information to justify clinical trials for the treatment of DPN with fish oils and salsalate.