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: 8053347
• 负责人: JEFFERY HUNTER YOUNG
• 金额: $ 41.58万
• 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/8053347
• 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。这一负担的后果是众所周知的。与非糖尿病患者相比，美国糖尿病患者死亡和发生血管和感染并发症的风险更大。2型糖尿病的患病率已经增加，这是美国超重和肥胖个体数量呈指数上升的直接结果。虽然肥胖与2型糖尿病的联系机制尚不确定，但肥胖增加与胰岛素抵抗密切相关，胰岛素抵抗是与2型糖尿病发展相关的关键生理紊乱。胰岛素抵抗还与年龄较大和体力活动减少有关，这是2型糖尿病的明确先兆。尽管有证据表明这些危险因素与胰岛素抵抗和随后的2型糖尿病有关，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，通过氧化过程代谢葡萄糖的能力降低（即线粒体功能障碍）在胰岛素抵抗的发展中起着重要作用。例如，许多小动物和临床研究表明，基因突变、氧化应激、异常线粒体形态、氧化基因表达减少、氧化磷酸化降低和有氧代谢能力低与肥胖、胰岛素抵抗和2型糖尿病相关。尽管关于能量稳态在代谢紊乱中的重要性正在形成共识，但在基于大规模人群的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（例如乳酸盐、丙氨酸、琥珀酸盐和1-酮戊二酸盐）水平是线粒体功能障碍的指标。因此，这些分子可能是有用的工具，在线粒体功能障碍和代谢紊乱之间的关系的调查。基于这一证据，我们假设线粒体功能障碍，通过测量参与葡萄糖代谢和能量产生的分子进行评估，与2型糖尿病和其他葡萄糖升高状态相关。为了验证这一假设，我们建议在社区动脉粥样硬化风险（ARIC）研究中测量这些因素，该研究是对来自4个美国社区的约15，000名成年人动脉粥样硬化的持续调查。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型糖尿病发病状态之间的关系。如果我们的假设是正确的，我们的研究应该：1）证实线粒体功能障碍在糖尿病中的重要性2）提供流行病学或临床环境中评估线粒体功能障碍的第一套工具，3）确定氧化能力降低的风险因素，4）确定与线粒体功能障碍相关的遗传变异。 公共卫生相关性：2型糖尿病的患病率由于肥胖的指数上升而显著增加。尽管它的重要性，负责2型糖尿病的潜在机制仍然知之甚少。在这项研究中，我们的目标是研究通过氧化过程代谢葡萄糖的能力降低在糖尿病中的作用，这项基于人群的研究包括来自4个美国社区的约15，000人。如果成功，这项工作可能会导致新的方法来评估糖尿病及其并发症的风险在临床上和新的方法来预防和治疗糖尿病。