Effects of fish oil and alpha lipoic on the progression of insulin resistance

描述(申请人提供)：肥胖率正在上升。即使是中度肥胖也可能导致代谢综合征的病理特征的发展。胰岛素抵抗是代谢综合征的基本特征，与β细胞功能障碍一起导致2型糖尿病(T2 DM)。由于代谢综合征和T2 DM的发病率不断上升，而且目前的治疗方法预防其长期并发症的能力有限，显然需要更多地关注胰岛素抵抗的一级预防。在这项应用中，我们建议检查补充鱼油和α硫辛酸的长期(1年)效果；这两种广泛使用的营养补充剂已知可激活PPAR和/或靶向脂质失调、炎症和氧化应激；以防止或减缓代谢综合征的非人类灵长类动物模型中胰岛素抵抗和血脂异常的进展。肥胖恒河猴的胰岛素抵抗的发展与人类代谢性疾病的进展具有相似的特征。我们之前已经证明，每天给肥胖的恒河猴提供含糖饮料，同时随意获得1年的正常饮食，会导致适度的体重和体脂增加，并伴随着胰岛素抵抗和血脂异常的快速进展(甘油三酯升高和高密度脂蛋白水平降低)。使用这一模型，确保严格控制和遵守饮食和补充剂摄入量，将使我们能够确定长期补充鱼油/硫辛酸在代谢综合征进展中的影响。我们将追求以下具体目标：具体目标1：我们假设补充鱼油将激活PPARα、γ和Delta，并防止或减缓胰岛素抵抗的进展。具体目标2：我们假设补充α-硫辛酸将减少氧化应激，防止或减缓胰岛素抵抗的进展。具体目标3：我们还将研究α-硫辛酸与鱼油PPAR激活剂(EPA和DHA)联合使用是否会比单独使用鱼油或α-硫辛酸预防糖尿病更有效。此外，我们将评估这些补充剂对一些与胰岛素抵抗和心血管疾病风险相关的脂质、氧化应激和炎症参数的影响，包括底物氧化、载脂蛋白-B、脂蛋白颗粒大小、脂联素、C-反应蛋白、同型半胱氨酸、白细胞介素6、肿瘤坏死因子-α、可溶性黏附因子和PAI-1。

DESCRIPTION (provided by applicant): The prevalence of obesity is rising. Even moderate obesity can contribute to the development of the pathological characteristics of the Metabolic Syndrome. Insulin resistance is the underlying characteristic of Metabolic Syndrome and, along with beta-cell dysfunction, results in Type 2 Diabetes Mellitus (T2DM). Due to the rising incidence of Metabolic Syndrome and T2DM and the limited ability of current treatments to prevent their long-term complications, it is clear that more attention needs to be focused on primary prevention of insulin resistance. In this application we propose to examine the long-term (1 year) effects of supplementation with fish oil and alpha lipoic acid; two widely used nutritional supplements known to activate PPARs and/or target lipid dysregulation, inflammation, and oxidative stress; to prevent or attenuate the progression of insulin resistance and dyslipidemia in a nonhuman primate model of the Metabolic Syndrome. The development of insulin resistance in obese rhesus monkeys shares similar features with the progression of metabolic disease in humans. We have previously demonstrated that providing obese rhesus monkeys with a sugar-sweetened beverage daily in combination with ad libitum access to their normal diet for 1 year results in modest weight and body fat gain accompanied by a rapid progression of insulin resistance and dyslipidemia (elevated triglyceride and reduced HDL levels). The use of this model in which rigorous control and compliance with diet and supplement intake can be ensured will allow us to determine the effects of long-term fish oil/lipoic acid supplementation in the progression of the Metabolic Syndrome. We will pursue the following specific aims: Specific Aim 1: We hypothesize that supplementation with fish oil will activate PPAR alpha, gamma and delta and prevent or attenuate the progression of insulin resistance. Specific Aim 2: We hypothesize that supplementation with alpha-lipoic acid will reduce oxidative stress and prevent or attenuate the progression of insulin resistance. Specific Aim 3: We will also investigate whether alpha-lipoic acid in combination with the fish oil PPAR activators (EPA & DHA) will be more effective than either fish oil or alpha- lipoic acid alone in preventing diabetes. In addition, we will assess the effects of the supplements on a number of lipid, oxidative stress and inflammatory parameters associated with insulin resistance and cardiovascular disease risk including substrate oxidation, apolipoprotein-B, lipoprotein particle size, adiponectin, C-reactive protein, homocysteine, interleukin-6, tumor necrosis factor-alpha, soluble adhesion factors, and PAI-1.