Longitudinal Study of Markers of Oxidative Capacity and Type 2 Diabetes

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、发生血管和感染性并发症的风险要大得多。2型糖尿病的发病率上升是美国超重和肥胖人数呈指数增长的直接结果。尽管肥胖与2型糖尿病之间的联系机制尚不确定，但肥胖的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一种关键生理紊乱。胰岛素抵抗也与老年和体力活动减少有关，这是2型糖尿病的前兆。尽管有强有力的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下降（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、线粒体形态异常、氧化基因表达减少、氧化磷酸化降低和有氧能力低下与肥胖、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的共识正在形成，但在基于大规模人群的研究或临床人群中，尚无可行的方法来评估线粒体功能。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（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与代谢紊乱之间关系的有用工具。基于这些证据，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来评估）与2型糖尿病和其他血糖升高状态有关。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，这是一项正在进行的对来自美国4个社区的约15,000名成年人的动脉粥样硬化调查。我们的目的是评估乳酸、丙氨酸、琥珀酸和1-酮戊二酸与血糖升高和2型糖尿病的关系。如果我们的假设是正确的，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)在流行病学或临床环境中提供第一套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)确定与线粒体功能障碍相关的遗传变异。

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.