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）：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-确定饮食中影响代谢状态的生物活性宏量营养素。2型糖尿病在西方流行。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，既能预测糖尿病的发病，也能促进糖尿病的发病。虽然目前有几类药物用于提高胰岛素敏感性，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、糖尿病和整体心血管风险有关。虽然这种饮食中的“活性成分”仍不确定，但最近的研究表明，简单的硝酸盐（NO3-）在代谢为亚硝酸盐（NO2-）后，支持信号介质的生成。初步数据表明，线粒体作为一个“生物反应器”，催化蛋白质和脂质被NO2-修饰，产生有益的细胞信号物质，包括s -亚硝化蛋白和硝化脂质，它们调节基本的生理事件。具体来说，这些物种可以通过翻译后蛋白修饰和核脂质受体PPAR3的激活来调节线粒体功能和炎症相关基因的表达。本文假设膳食硝酸盐是一种具有生物活性的膳食营养素，可转化为调节氧化炎症反应和代谢的物质，激活PPAR3，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，他们在氧化还原依赖的细胞信号，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测试这一假设。膳食硝酸盐对胰岛素敏感性的影响将在长期插管的野生型和肥胖小鼠中使用一种新的技术，即频繁采样静脉内葡萄糖耐量试验和高胰岛素正糖钳。通过有针对性的生化方法，将获得关于膳食NO3-和NO2-如何通过线粒体氧化还原反应影响胰岛素分泌和敏感性的详细机制。从这项研究中获得的知识将启动对胰岛素敏感性机制的新理解和治疗T2D的新药理学策略。对这种富含“心脏健康”食物的膳食分子的信号反应进行表征，将提高人们对简单的生活方式改变如何在管理和预防胰岛素敏感性方面产生深远益处的普遍理解，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型糖尿病在西方化人群中流行，胰岛素抵抗有助于糖尿病的发病。