Dietary nitrate activation of PPARgamma improves insulin sensitivity

膳食硝酸盐激活 PPARgamma 可提高胰岛素敏感性

• 批准号: 7938780
• 负责人: Bruce Alan Freeman
• 金额: $ 49.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938780
• 关键词: Address; Adipose tissue; Area; Arts; Basic Science; Biochemical; Biology; Bioreactors; Cardiovascular system; Clinical; Commit; Conscious; Data; Diabetes Mellitus; Diet; Dietary Factors; Disease; Employee Strikes; Epidemic; Euglycemic Clamping; Event; Fatty Acids; Fishes; Food; Foundations; Gene Expression; General Population; Generations; Genes; Glucose Clamp; Guidelines; Heart; Heart failure; Human; In Vitro; Infarction; Inflammatory; Insulin Resistance; Knowledge; Lead; Life Style; Lipids; Macronutrients Nutrition; Measures; Mediating; Mediator of activation protein; Mediterranean Diet; Metabolic; Metabolism; Mitochondria; Mus; NBL1 gene; Nitrates; Nitric Oxide; Nitrites; Nitrogen Oxides; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obese Mice; Obesity; Organ; Oxidation-Reduction; Oxidative Stress; PPAR gamma; Peripheral; Pharmaceutical Preparations; Physicians; Physiological; Play; Population; Post-Translational Protein Processing; Proteins; Reaction; Reactive Oxygen Species; Regulation; Research; Research Personnel; Role; Salivary; Sampling; Signal Transduction; Skeletal Muscle; Sodium Chloride; Solid; Structure of beta Cell of islet; Techniques; Testing; Therapeutic; Tissues; Training; Translational Research; Vegetables; Work; abstracting; base; cardiovascular risk factor; dietary nitrate; good diet; improved; in vivo; insulin secretion; insulin sensitivity; intravenous administration; intravenous glucose tolerance test; member; novel; novel therapeutics; prevent; receptor; stem

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.

描述（由申请人提供）：此申请应解决广泛的挑战领域（15）转化科学和特定挑战主题，15-DK-101-鉴定饮食中影响代谢状态的生物活性大量营养素。 2型糖尿病是西方人群的流行病。胰岛素耐药性部分源于以线粒体为中心的“氧化应激”状态，是一个早期事件，既预测并有助于糖尿病的发作。尽管目前开了几类药物以增强胰岛素敏感性，但这些疗法受到不良心血管事件（包括心力衰竭和梗塞）的倾向增加而阻碍。富含多叶绿色蔬菜和鱼类的饮食，例如地中海饮食，与肥胖，糖尿病和整体心血管风险的显着降低有关。尽管这种饮食中的“活性成分”仍然不确定，但最近的研究表明，简单的硝酸盐（NO3-）在代谢对亚硝酸盐（NO2-）后支持信号介质的产生。初步数据表明，线粒体充当一种“生物反应器”，可通过NO2-催化蛋白质和脂质的修饰，产生用于调节基本物理学事件的硅质细胞信号传导物种，包括S-硝化蛋白质和硝化脂质。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PPAR3的激活来调节线粒体功能和炎症相关基因的表达。在这里，假设饮食硝酸盐是一种生物活性饮食营养素，转化为调节氧化炎性反应和代谢的物种，并激活PPAR3，从而提高胰岛素敏感性。由基本和临床生理学家和生物化学家组成的强大团队，在氧化还原依赖性细胞信号，心血管生物学和糖尿病方面具有专业知识，已经制定了一项易于可执行的研究计划，以检验该假设。硝酸饮食硝酸盐对胰岛素敏感性的影响将通过一种新型技术进行测试，该技术经常采样静脉内葡萄糖耐受性测试和高胰岛素血症纤维血糖夹在慢性导管的野生型和肥胖小鼠中。关于饮食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，将使用针对性的生化方法获得详细的机械理解。从这项研究中获得的知识将对胰岛素敏感性的基础机制和治疗T2D的新型药理策略产生新的理解。在“心脏健康”食品中丰富的这种饮食分子的信号反应的表征将提高人们对简单生活方式变化的一般理解，从而为管理和预防胰岛素敏感性带来深远的好处，从而增加了普通人群成员对这些持续的生活方式变化的可能性。 2型糖尿病在西方种群中流行，胰岛素抵抗有助于糖尿病的发作。 公共卫生相关性：一种称为硝酸盐的分子，在绿叶蔬菜和健康饮食的其他成分中发现，可能在预防和逆转胰岛素抵抗方面起重要作用。了解硝酸盐如何与糖尿病有关，将帮助研究人员和医生为糖尿病患者制定基于科学的饮食指南。