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）转化科学和特定的挑战主题，15-DK-101-饮食中影响代谢状态的生物活性常量营养素的鉴定。2型糖尿病在西方人群中流行。胰岛素抵抗，部分源于线粒体中的“氧化应激”状态，是预测和促成糖尿病发作的早期事件。虽然目前有几类药物用于增强胰岛素敏感性，但这些治疗受到不良心血管事件（包括心力衰竭和梗死）倾向增加的阻碍。富含多叶绿色蔬菜和鱼类的饮食，如地中海饮食，与肥胖、糖尿病和总体心血管风险的显著降低有关。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，支持信号介质的产生。初步数据表明，该酶作为一个“生物反应器”，催化NO2-修饰蛋白质和脂质，产生有益的细胞信号种类，包括S-亚硝化蛋白质和硝化脂质，调节基本的生理事件。具体而言，这些物种可以通过翻译后蛋白质修饰和核脂质受体PPAR 3的活化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膳食营养素，其转化为调节氧化炎症反应和代谢并激活PPAR 3的物质，从而增加胰岛素敏感性。一个强大的基础和临床生理学家和生物化学家团队，在氧化还原依赖性细胞信号传导，心血管生物学和糖尿病方面具有专业知识，他们设计了一个易于执行的研究计划来验证这一假设。将使用频繁采样的静脉内葡萄糖耐量试验和高胰岛素血症正葡萄糖钳夹的新技术，在长期插管的野生型和肥胖小鼠中测试饮食硝酸盐对胰岛素敏感性的影响。将获得详细的机制的理解，使用有针对性的生化方法，关于如何饮食NO3-和NO2-可以通过线粒体氧化还原反应影响胰岛素分泌和敏感性。从这项研究中获得的知识将开始对胰岛素敏感性的机制和治疗T2 D的新药理学策略进行新的理解。表征这种富含“心脏健康”食物的饮食分子的信号反应将提高对简单生活方式改变如何产生管理和预防胰岛素敏感性的深远益处的一般理解，从而增加普通人群成员致力于这些持续生活方式改变的可能性。2型糖尿病在西方化人群中流行，胰岛素抵抗有助于糖尿病的发病。 公共卫生相关性：在多叶绿色蔬菜和健康饮食的其他成分中发现的一种称为硝酸盐的分子，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.