Longitudinal study of markers of oxidative capacity and type 2 diabetes

氧化能力和 2 型糖尿病标志物的纵向研究

• 批准号: 7777433
• 负责人: JEFFERY HUNTER YOUNG
• 金额: $ 52.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-30 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777433
• 关键词: Adult; Aerobic; Age; Alanine; American; Ancillary Study; Animals; Area; Arts; Atherosclerosis; Automobile Driving; Biological Markers; Blood; Blood Pressure; Blood Vessels; Citric Acid Cycle; Clinic; Clinical; Clinical Research; Communities; Consensus; Data; Data Set; Development; Diabetes Mellitus; Diabetes prevention; Epidemiologic Studies; Epidemiology; Gene Expression; Gene Mutation; Genetic; Genetic Markers; Genetic Variation; Genotype; Glucose; Glycolysis; Goals; Homeostasis; Hyperglycemia; Individual; Insulin; Insulin Resistance; Investigation; Lead; Life Style; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; Mitochondria; Morphology; Muscle; NMR Spectroscopy; National Health and Nutrition Examination Survey; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Oxidative Phosphorylation; Oxidative Stress; Participant; Pathway interactions; Physical activity; Physiological; Plasma; Play; Population; Prediabetes syndrome; Prevalence; Process; Production; Publishing; Reporting; Risk; Risk Factors; Role; Succinates; Testing; Tissues; United States; Urine; Visit; Work; base; cohort; diabetes risk; fasting glucose; genetic variant; genome wide association study; genome-wide analysis; glucose metabolism; metabolomics; middle age; mitochondrial dysfunction; non-diabetic; novel; novel strategies; population based; public health relevance; sedentary; tool; urinary

DESCRIPTION (provided by applicant): In the United States, over 40% of adults have diabetes or pre-diabetes according to recently published NHANES data. The consequences of this burden are well-known. Compared to their non-diabetic counterparts, Americans with diabetes are at much greater risk to die and to develop vascular and infectious complications. The prevalence of type 2 diabetes has increased as a direct result of the exponential rise in the number of overweight and obese individuals in the United States. Although the mechanisms linking obesity with type 2 diabetes are uncertain, increased adiposity is closely tied to insulin resistance, a key physiologic derangement connected to the development of type 2 diabetes. Insulin resistance is also associated with older age and decreased physical activity, well-established antecedents of type 2 diabetes. Despite the strength of the evidence linking these risk factors with insulin resistance and subsequent type 2 diabetes, the underlying mechanism driving insulin resistance is not well understood. Accumulating evidence suggests, however, that decreased capacity to metabolize glucose via oxidative processes (i.e. mitochondrial dysfunction) plays a fundamental role in the development of insulin resistance. For example, a number of small animal and clinical studies have shown that genetic mutations, oxidative stress, abnormal mitochondrial morphology, diminished oxidative gene expression, decreased oxidative phosphorylation, and low aerobic capacity are associated with obesity, insulin resistance, and type 2 diabetes. Despite the emerging consensus regarding the importance of energy homeostasis in metabolic disorders, there are no feasible methods for assessing mitochondrial function in large population-based studies or in clinical populations. Recent evidence suggests, however, that blood and urine levels of molecules involved in glucose metabolism (e.g. lactate, alanine, succinate, and 1- ketoglutarate) are indicators of mitochondrial dysfunction. Therefore, these molecules may be useful tools in the investigation of the relationship between mitochondrial dysfunction and metabolic disorders. Based on this evidence, we hypothesize that mitochondrial dysfunction, assessed by measuring molecules involved in glucose metabolism and energy production is associated with type 2 diabetes and other states of elevated glucose. To test this hypothesis, we propose to measure these factors in the Atherosclerosis Risk in Communities (ARIC) Study, an on-going investigation of atherosclerosis among approximately 15,000 adults from 4 U.S. communities. Our goal is to assess the association of lactate, alanine, succinate, and 1- ketoglutarate with states of elevated glucose and incident type 2 diabetes. If our hypothesis is correct, our study should: 1) confirm the importance of mitochondrial dysfunction in diabetes 2) offer the first set of tools for assessing mitochondrial dysfunction in an epidemiologic or clinical setting, 3) identify risk factors for decreased oxidative capacity and 4) identify genetic variants associated with mitochondrial dysfunction. PUBLIC HEALTH RELEVANCE: The prevalence of type 2 diabetes has increased markedly due to the exponential rise in obesity. Despite its importance, the underlying mechanisms responsible for type 2 diabetes are still poorly understood. In this study, our goal is to examine the role that decreased capacity to metabolize glucose via oxidative processes plays in diabetes in a population-based study consisting of approximately 15,000 people from 4 U.S. communities. If successful, this work could lead to new ways to assess risk for diabetes and its complications in the clinic and to novel approaches for diabetes prevention and treatment.

描述（由申请人提供）：在美国，根据最近发布的NHANES数据，超过40％的成年人患有糖尿病或糖尿病前。这种负担的后果是众所周知的。与非糖尿病的非糖尿病患者相比，患有糖尿病的美国人死亡和发展血管和感染性并发症的风险要大得多。 2型糖尿病的患病率是由于美国超重和肥胖个体的指数增加的直接结果。尽管将肥胖与2型糖尿病联系起来的机制尚不确定，但肥胖的增加与胰岛素抵抗密切相关，这是与2型糖尿病发展有关的关键生理危险。胰岛素抵抗也与年龄较大和体育活动减少有关，即2型糖尿病的前提。尽管有证据将这些危险因素与胰岛素抵抗和随后的2型糖尿病联系起来，但驱动胰岛素抵抗的基本机制尚不清楚。然而，积累的证据表明，通过氧化过程（即线粒体功能障碍）降低了代谢葡萄糖的能力，在胰岛素抵抗的发展中起着基本作用。例如，许多小动物和临床研究表明，遗传突变，氧化应激，异常线粒体形态，氧化基因表达降低，氧化磷酸化降低和低氧能力与肥胖，胰岛素抵抗，胰岛素抵抗和2型糖尿病有关。尽管关于能量稳态在代谢性疾病中的重要性的新兴共识，但在大型基于人群的研究或临床人群中，没有可行的方法来评估线粒体功能。然而，最近的证据表明，参与葡萄糖代谢的分子的血液和尿液水平（例如乳酸，丙氨酸，琥珀酸酯和1-酮戊二酸）是线粒体功能障碍的指标。因此，这些分子可能是研究线粒体功能障碍与代谢性疾病之间关系的有用工具。基于这一证据，我们假设通过测量参与葡萄糖代谢和能量产生的分子评估的线粒体功能障碍与2型糖尿病和其他葡萄糖升高的状态有关。为了检验这一假设，我们建议在社区（ARIC）研究的动脉粥样硬化风险中衡量这些因素，这是对来自美国4个社区的大约15,000名成年人的动脉粥样硬化的持续研究。我们的目标是评估乳酸，丙氨酸，琥珀酸酯和1-酮戊二酸与葡萄糖升高和2型糖尿病入射的状态的关联。如果我们的假设是正确的，我们的研究应：1）确认糖尿病中线粒体功能障碍的重要性2）提供了评估线粒体功能障碍在流行病学或临床环境中的第一组工具，3）3））识别氧化能力降低的危险因素，并确定与遗传变异的危险因素相关。 公共卫生相关性：由于肥胖症的指数增长，2型糖尿病的患病率显着增加。尽管它的重要性，但负责2型糖尿病的基本机制仍然很少了解。在这项研究中，我们的目标是研究通过氧化过程在糖尿病中发挥作用的能力来降低糖尿病的能力，该研究由来自美国4个社区的大约15,000人组成的人群研究中。如果成功，这项工作可能会导致新的方法来评估糖尿病风险及其在诊所中的并发症以及预防糖尿病预防和治疗的新方法。