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: 8235034
• 负责人: JEFFERY HUNTER YOUNG
• 金额: $ 44.34万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235034
• 关键词: Adult; Aerobic; Age; Alanine; American; Ancillary Study; Animals; Area; 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; 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）：根据最近公布的 NHANES 数据，在美国，超过 40% 的成年人患有糖尿病或糖尿病前期。这种负担的后果是众所周知的。与非糖尿病患者相比，患有糖尿病的美国人死亡以及发生血管和感染并发症的风险要大得多。 2 型糖尿病的患病率增加是美国超重和肥胖人数呈指数级增长的直接结果。尽管肥胖与 2 型糖尿病之间的联系机制尚不确定，但肥胖增加与胰岛素抵抗密切相关，而胰岛素抵抗是与 2 型糖尿病发展相关的一种关键生理紊乱。胰岛素抵抗还与年龄较大和体力活动减少有关，这些都是 2 型糖尿病的既定前因。尽管有充分的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潜在机制尚不清楚。然而，越来越多的证据表明，通过氧化过程（即线粒体功能障碍）代谢葡萄糖的能力下降在胰岛素抵抗的发展中起着重要作用。例如，大量小动物和临床研究表明，基因突变、氧化应激、线粒体形态异常、氧化基因表达减少、氧化磷酸化减少和有氧能力低与肥胖、胰岛素抵抗和2型糖尿病有关。尽管关于能量稳态在代谢紊乱中的重要性正在形成共识，但在大规模人群研究或临床人群中没有评估线粒体功能的可行方法。然而，最近的证据表明，血液和尿液中参与葡萄糖代谢的分子（例如乳酸、丙氨酸、琥珀酸和 1-酮戊二酸）水平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和代谢紊乱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来评估线粒体功能障碍与 2 型糖尿病和其他血糖升高状态相关。为了检验这一假设，我们建议在社区动脉粥样硬化风险 (ARIC) 研究中衡量这些因素，该研究正在进行中，对来自 4 个美国社区的约 15,000 名成年人进行动脉粥样硬化调查。我们的目标是评估乳酸、丙氨酸、琥珀酸和 1-酮戊二酸与血糖升高和 2 型糖尿病发生的关系。如果我们的假设正确，我们的研究应该：1) 确认线粒体功能障碍在糖尿病中的重要性 2) 提供第一套在流行病学或临床环境中评估线粒体功能障碍的工具，3) 确定氧化能力下降的危险因素，4) ）识别与线粒体功能障碍相关的遗传变异。 公共卫生相关性：由于肥胖指数呈指数上升，2 型糖尿病的患病率显着增加。尽管它很重要，但人们对 2 型糖尿病的潜在机制仍知之甚少。在这项研究中，我们的目标是在一项由来自 4 个美国社区的约 15,000 人组成的基于人群的研究中，探讨氧化过程中葡萄糖代谢能力下降在糖尿病中所起的作用。如果成功，这项工作可能会带来在临床上评估糖尿病及其并发症风险的新方法，以及糖尿病预防和治疗的新方法。

项目成果

The association of plasma lactate with incident cardiovascular outcomes: the ARIC Study.

血浆乳酸与心血管事件的关联：ARIC 研究。

• 发表时间: 2013-08-01
• 影响因子: 5
• 作者: Matsushita, Kunihiro;Williams, Emma K;Mongraw;Coresh, Josef;Schmidt, Maria Ines;Brancati, Frederick L;Hoogeveen, Ron C;Ballantyne, Christie M;Young, J Hunter
• 通讯作者: Young, J Hunter

Association of blood lactate with carotid atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study.

血乳酸与颈动脉粥样硬化的关联：社区动脉粥样硬化风险 (ARIC) 颈动脉 MRI 研究。

• DOI: 10.1016/j.atherosclerosis.2013.02.014
• 发表时间: 2013-05
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Shantha, Ghanshyam Palamaner Subash;Wasserman, Bruce;Astor, Brad C.;Coresh, Josef;Brancati, Fredrick;Sharrett, A. Richey;Young, J. Hunter
• 通讯作者: Young, J. Hunter