EFFECTS OF FISH OIL AND ALPHA-LIPOIC ACID ON THE PROGR OF INSUL RESIST

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖症的流行率正在显著增加。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基本特征，并且沿着β细胞功能障碍，导致2型糖尿病（T2 DM）。由于代谢综合征和2型糖尿病的发病率不断上升，目前的治疗方法预防其长期并发症的能力有限，因此显然需要更多地关注胰岛素抵抗的一级预防。在本申请中，我们提出在饮食诱导的胰岛素抵抗的非人灵长类动物模型中研究鱼油和<$-硫辛酸补充剂单独和组合预防或减弱胰岛素抵抗和血脂异常进展的长期（1年）作用。肥胖恒河猴胰岛素抵抗的发展与人类代谢性疾病的进展具有相似的特征。我们之前已经证明，每天给肥胖的恒河猴提供含糖饮料，并随意获得正常饮食，持续1年，导致适度的体重和体脂增加，伴随着胰岛素抵抗和血脂异常的快速进展（甘油三酯升高和HDL水平降低）。该模型的使用可以确保严格控制和遵守饮食和补充剂的摄入，这将使我们能够确定长期服用鱼油和<$-硫辛酸对胰岛素抵抗和血脂异常的发展和进展的影响。我们建议在这种非人灵长类动物模型中确定两种广泛使用的已知激活PPARs和/或靶向脂质失调、炎症（鱼油）和氧化应激（α-硫辛酸）的营养补充剂的功效。 我们将追求以下具体目标：具体目标1：测试补充鱼油将激活PPARalpha，gamma和delta，增加血浆脂联素水平，并预防或减轻胰岛素抵抗的进展的假设。具体目标二：验证以下假设：补充有效的抗氧化剂α-硫辛酸将减少氧化应激，预防或减轻胰岛素抵抗的进展。具体目标3：检验鱼油与α-硫辛酸组合的效果将大于鱼油或α-硫辛酸单独使用的假设。此外，我们将确定补充剂对脂质、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、可溶性粘附因子和派-1。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.