EFF OF FISH OIL AND ALPHA-LIPOIC ACID ON THE PROGR OF INSULIN RESIST

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 肥胖症的患病率正在显著增加。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，我们建议在饮食诱导的胰岛素抵抗的非人灵长类动物模型中，研究单独和联合补充鱼油和硫辛酸的长期(1年)效果，以防止或减轻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服用鱼油和硫辛酸对胰岛素抵抗和血脂异常的发展和进展的影响。我们建议确定两种广泛使用的营养补充剂在这个非人类灵长类动物模型中激活PPAR和/或靶向脂质失调、炎症(鱼油)和氧化应激(α-硫辛酸)的有效性。我们将追求以下特定目标：特定目标1：检验补充鱼油将激活PPARpha、Gamma和Delta的假设，提高血浆脂联素水平，防止或减缓胰岛素抵抗的进展。具体目标2：验证补充有效抗氧化剂α-硫辛酸将减少氧化应激并防止或减缓胰岛素抵抗进展的假设。具体目标3：检验鱼油与α-硫辛酸联合作用比单独使用鱼油或α-硫辛酸的影响更大的假设。此外，我们还将确定补充剂对血脂、氧化应激和与胰岛素抵抗和心血管风险相关的炎症参数的影响，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、单核细胞趋化蛋白-1、可溶性黏附因子和PAI-1。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The prevalence of obesity is increasing markedly. 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 investigate the long-term (1 year) effects of fish oil and ¿-lipoic acid supplementation, alone and in combination, to prevent or attenuate the progression of insulin resistance and dyslipidemia in a nonhuman primate model of diet-induced insulin resistance. 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 administration of fish oil and ¿-lipoic acid on the progression of thedevelopment and progression of insulin resistance and dyslipidemia. We propose to determine the efficacy of two widely used nutritional supplements known to activate PPARs and/or target lipid dysregulation, inflammation (fish oil), and oxidative stress (alpha-lipoic acid) in this nonhuman primate model. We will pursue the following specific aims: Specific Aim 1: Test the hypothesis that supplementation with fish oil will activate PPARalpha, gamma and delta, increase plasma adiponectin levels, and prevent or attenuate the progression of insulin resistance. Specific Aim 2: Test the hypothesis that supplementation with the potent anti-oxidant, alpha-lipoic acid will reduce oxidative stress and prevent or attenuate the progression of insulin resistance. Specific Aim 3: Test the hypothesis that the effects fish oil in combination with alpha-lipoic acid will be greater than either fish oil or alpha-lipoic acid alone. In addition, we will determine the effects of the supplements on lipid, oxidative stress and inflammatory parameters associated with insulin resistance and cardiovascular risk including substrate oxidation, apolipoprotein-B, lipoprotein particle size, adiponectin, C-reactive protein, homocysteine, interleukin-6, tumor necrosis factor-alpha, monocyte-chemoattractant protein-1, soluble adhesion factors, and PAI-1.