Dietary nitrate activation of PPARgamma improves insulin sensitivity

描述(由申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和具体的挑战主题，15-DK-101-识别饮食中影响代谢状态的生物活性微量营养素。2型糖尿病在西方人群中很流行。胰岛素抵抗，部分源于以线粒体为中心的“氧化应激”状态，是一种早期事件，既可以预测糖尿病的发生，也可以促进糖尿病的发生。虽然目前有几类药物被用来增强胰岛素敏感性，但这些治疗因不良心血管事件(包括心力衰竭和脑梗塞)倾向的增加而受到阻碍。富含绿叶蔬菜和鱼类的饮食，如地中海饮食，与显著降低肥胖、糖尿病和总体心血管风险有关。虽然这种饮食中的“活性成分”仍然不确定，但最近的研究表明，简单的硝酸盐(NO3-)在代谢为亚硝酸盐(NO2-)时，支持信号媒介的产生。初步数据显示，线粒体作为一个生物反应器，催化蛋白质和脂质被亚硝酸盐修饰，产生有益的细胞信号种类，包括S亚硝化的蛋白质和硝化的脂类，它们调节基本的生理事件。具体地说，这些物种可以通过翻译后蛋白修饰和核脂受体PPAR3的激活来调节线粒体功能和炎症相关基因的表达。这里假设膳食硝酸盐是一种生物活性的膳食营养物质，它被转化为调节氧化性炎症反应和新陈代谢的物种，并激活PPAR3，从而增加胰岛素敏感性。一支由基础和临床生理学家和生物化学家组成的强大团队，在氧化还原依赖细胞信号、心血管生物学和糖尿病方面具有专业知识，已经设计出一项易于执行的研究计划来测试这一假设。饮食中硝酸盐对胰岛素敏感性的影响将使用一种新的技术--频繁采样静脉葡萄糖耐量试验和高胰岛素正血糖钳夹技术在长期导管化的野生型和肥胖小鼠中进行测试。使用有针对性的生化方法，将获得详细的机制了解，关于饮食中的NO3-和NO2-如何通过线粒体氧化还原反应影响胰岛素的分泌和敏感性。从这项研究中获得的知识将开启对胰岛素敏感性潜在机制的新理解，并为治疗T2D提供新的药理学策略。对“心脏健康”食品中丰富的这种饮食分子的信号反应进行表征，将提高人们对简单生活方式改变如何为管理和预防胰岛素敏感性带来深远好处的总体理解，从而增加普通人群致力于这些持续生活方式改变的可能性。2型糖尿病在西方人中流行，胰岛素抵抗是糖尿病发病的原因之一。 与公共健康相关：在绿叶蔬菜和健康饮食的其他成分中发现的一种名为硝酸盐的分子，可能在预防和逆转胰岛素抵抗方面发挥重要作用。了解硝酸盐与糖尿病的关系将有助于研究人员和医生为糖尿病患者制定科学的饮食指南。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DK-101- Identification of bioactive macronutrients in the diet that impact metabolic state. Type 2 Diabetes is epidemic in western populations. Insulin resistance, stemming in part from a state of "oxidative stress" centered in mitochondria, is an early event that both predicts and contributes to the onset of diabetes. While several classes of drugs are currently prescribed to enhance insulin sensitivity, these therapies are hindered by an increased propensity for adverse cardiovascular events (including heart failure and infarction). Diets rich in leafy green vegetables and fish, such as the Mediterranean diet, are associated with a striking reduction in obesity, diabetes and overall cardiovascular risk. Although the "active ingredient" in this diet remains uncertain, recent studies demonstrate that the simple salt nitrate (NO3-), upon metabolism to nitrite (NO2-), supports the generation of signaling mediators. Preliminary data show that the mitochondrion acts as a "bioreactor" to catalyze the modification of proteins and lipids by NO2-, yielding salutary cell signaling species including S-nitrosated proteins and nitrated lipids, which regulate fundamental physiological events. Specifically, these species can regulate mitochondrial function and the expression of inflammatory-related genes via post-translational protein modification and activation of the nuclear lipid receptor PPAR3. Here it is hypothesized that dietary nitrate is a bioactive dietary nutrient that is converted to species that modulate oxidative inflammatory reactions and metabolism and activates PPAR3, thereby increasing insulin sensitivity. A strong team of basic and clinical physiologists and biochemists with expertise in redox-dependent cell signaling, cardiovascular biology and diabetes has devised a readily executable research plan to test this hypothesis. The effect of dietary nitrate on insulin sensitivity will be tested using a novel technique of frequently sampled intravenous glucose tolerance tests and hyperinsulinemic euglycemic clamps in chronically catheterized wild type and obese mice. Detailed mechanistic understanding will be obtained, using a targeted biochemical approach, regarding how dietary NO3- and NO2- can influence insulin secretion and sensitivity via mitochondrial redox reactions. The knowledge gained from this study will initiate a new understanding of mechanisms underlying insulin sensitivity and a novel pharmacologic strategy for treating T2D. Characterization of the signaling reactions of this dietary molecule abundant in "heart-healthy" foods will improve the general understanding of how simple lifestyle changes can yield profound benefit for managing and preventing insulin sensitivity, thereby increasing the likelihood that members of the general population will commit to these sustained lifestyle changes. Type 2 Diabetes is epidemic in westernized populations and insulin resistance contributes to the onset of diabetes. PUBLIC HEALTH RELEVANCE: A molecule called nitrate, found in leafy green vegetables and other components of a healthy diet, may play an important role in preventing and reversing insulin resistance. Understanding how nitrate works with regards to diabetes will help researchers and physicians develop scientifically-based dietary guidelines for people with diabetes.