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

描述（由申请人提供）：肥胖的患病率正在上升。即使是中度肥胖也可能导致代谢综合征病理特征的发展。胰岛素抵抗是代谢综合征的潜在特征，并与β细胞功能障碍一起导致2型糖尿病（T2DM）。由于代谢综合征和2型糖尿病的发病率不断上升，而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。在本应用中，我们建议检查补充鱼油和α硫辛酸的长期（1年）效果；两种广泛使用的营养补充剂，已知可激活ppar和/或针对脂质失调、炎症和氧化应激；在代谢综合征的非人类灵长类动物模型中预防或减轻胰岛素抵抗和血脂异常的进展。肥胖恒河猴胰岛素抵抗的发展与人类代谢疾病的发展具有相似的特征。我们之前已经证明，每天给肥胖的恒河猴提供一种含糖饮料，并随意给予其正常饮食1年，结果是适度的体重和体脂增加，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）。使用这个模型，严格控制和遵守饮食和补充剂的摄入，可以确保我们确定长期补充鱼油/硫辛酸对代谢综合征进展的影响。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PPAR α， γ和δ并预防或减轻胰岛素抵抗的进展。具体目的2：我们假设补充α -硫辛酸可以减少氧化应激，防止或减轻胰岛素抵抗的进展。具体目标3：我们还将研究α -硫辛酸与鱼油PPAR活化剂（EPA和DHA）联合使用是否比单独使用鱼油或α -硫辛酸更有效地预防糖尿病。此外，我们将评估补充剂对与胰岛素抵抗和心血管疾病风险相关的许多脂质、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、可溶性粘附因子和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.