Quantitative in vivo biomarkers of oxidative stress in diabetes

糖尿病氧化应激的定量体内生物标志物

• 批准号: 7449435
• 负责人: In-Young Choi
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449435
• 关键词: Antioxidants; Ascorbic Acid; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Caring; Cellular Stress; Cerebrum; Chemical Shift Imaging; Chronic; Clinical Research; Communities; Complications of Diabetes Mellitus; Condition; Defense Mechanisms; Development; Diabetes Mellitus; Disease; Disease Progression; Evaluation; Free Radicals; Glucose; Glutathione; Human; Hyperglycemia; Image; Imaging Techniques; In Situ; Inflammation; Insulin; Insulin Resistance; Invasive; Lead; Life; Magnetic Resonance; Malignant Neoplasms; Maps; Measurable; Measurement; Measures; Medical; Metabolic; Methods; Mitochondria; Monitor; Natural regeneration; Nerve Degeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathologic Processes; Patients; Peripheral; Physiological; Play; Predisposition; Public Health; Reactive Oxygen Species; Resistance; Role; Scurvy; System; Techniques; Therapeutic; Tissues; antioxidant therapy; ascorbate; base; brain tissue; diabetic; efficacy evaluation; glycemic control; improved; in vivo; insight; interest; intravenous administration; monocyte; neurochemistry; novel; quantum; tool; uptake

DESCRIPTION (provided by applicant): The overall aim of this proposal is to develop and characterize direct, objective in vivo biomarkers of oxidative stress occurring in diabetes mellitus. Such biomarkers would be valuable for monitoring long-term ongoing changes and complications that result from prolonged hyperglycemia and associated oxidative stress. We focus on two major antioxidants, glutathione (GSH) and vitamin C (ascorbate, Asc), that have received interest from the medical community as potential markers of oxidative stress to elucidate their role in diabetes and to provide new insights into diabetes care. Diabetes, one of the most common diseases in the US, is characterized by insulin insufficiency or resistance and hyperglycemia, which induce oxidative stress and lead to impaired antioxidant defense. GSH and Asc are the major antioxidants and play a central role in the antioxidant defense system. Also, there is a dynamic metabolic interaction between these antioxidants, which form the antioxidant network. GSH has been identified as a sensitive indicator of oxidative stress. Asc is the major antioxidant besides GSH, and has the neuroprotective role. Levels of Asc have been used as a marker for oxidative status in peripheral tissues and to evaluate the outcome of Asc treatments in diseases such as diabetes and cancer. To date, however, there has been no direct noninvasive measurement of GSH and Asc in any living tissues of the pathologic brain including diabetes due to the scarcity of available techniques. Therefore, the development of completely noninvasive and quantitative techniques for measuring these antioxidants would be a highly significant advance for accurate assessment. Recently we established the feasibility of GSH and Asc mapping in the human brain using novel magnetic resonance techniques: selective multiple quantum chemical shift imaging. Using these unique imaging techniques as a robust tool for clinical studies in diabetes, we will characterize the usefulness of our imaging approach by investigating cerebral antioxidant levels in situ. The aims of this project are: (1) to determine cerebral concentrations of two major antioxidants (GSH and Asc) in the living brains of normal controls and type 2 diabetic patients, and (2) to quantify the effect of chronic hyperglycemia on cellular uptake of Asc across the blood-brain barrier. A well characterized non-invasive biomarker of oxidative stress will not only provide new insights into the role of antioxidants in diabetes but also play a vital role in the development of therapeutic strategies and the evaluation of the efficacy of antioxidant treatments for diabetes. PUBLIC HEALTH RELEVANCE: The identification of a sensitive biomarker of oxidative stress in diabetes will provide a means to track the progression of the disease and the degree to which treatments are effective. Since a biomarker of oxidative stress may provide information on changes in antioxidant levels in the brain of diabetic patients, patients who are lacking in antioxidants can be identified and receive treatments. Therefore, complications resulting from diabetes will be reduced which will be an important factor in improving public health.

描述（由申请人提供）：该提案的总体目的是发展和表征糖尿病中发生的氧化应激的直接，客观的体内生物标志物。这种生物标志物对于监测长期高血糖和相关氧化应激导致的长期持续变化和并发症将很有价值。我们专注于两种主要的抗氧化剂，分别是谷胱甘肽（GSH）和维生素C（Ascorbate，ASC），它们引起了医学界的兴趣，作为氧化应激的潜在标志，以阐明其在糖尿病中的作用，并为糖尿病护理提供新的见解。糖尿病是美国最常见的疾病之一，其特征是胰岛素功能不全或耐药性和高血糖症，可诱导氧化应激并导致抗氧化剂防御受损。 GSH和ASC是主要的抗氧化剂，在抗氧化剂防御系统中起着核心作用。同样，这些抗氧化剂之间存在动态代谢相互作用，形成了抗氧化剂网络。 GSH已被确定为氧化应激的敏感指标。 ASC除了GSH以外是主要的抗氧化剂，并且具有神经保护作用。 ASC的水平已被用作外周组织中氧化状态的标记，并评估糖尿病和癌症等疾病中ASC治疗的结果。然而，迄今为止，由于可用技术的稀缺性，在包括糖尿病的任何活性组织中，还没有直接对GSH和ASC进行直接无创测量。因此，用于测量这些抗氧化剂的完全无创和定量技术的开发将是准确评估的高度重大进步。最近，我们使用新型的磁共振技术确定了人脑中GSH和ASC映射的可行性：选择性多重量子化学移动成像。使用这些独特的成像技术作为糖尿病临床研究的强大工具，我们将通过研究原位脑抗氧化剂水平来表征成像方法的有用性。该项目的目的是：（1）确定正常对照组和2型糖尿病患者的活体大脑中两种主要抗氧化剂（GSH和ASC）的脑浓度，以及（2）量化慢性高血糖对ASC细胞在血液障碍遍布ASC摄取的影响。具有良好特征的氧化应激的非侵入性生物标志物将不仅可以为抗氧化剂在糖尿病中的作用提供新的见解，而且还可以在治疗策略的发展中起着至关重要的作用，并评估抗氧化剂治疗糖尿病的疗效。 公共卫生相关性：鉴定糖尿病中氧化应激的敏感生物标志物将提供一种方法来跟踪疾病进展以及治疗有效的程度。由于氧化应激的生物标志物可以提供有关糖尿病患者大脑中抗氧化剂水平变化的信息，因此可以鉴定缺乏抗氧化剂的患者并接受治疗。因此，糖尿病引起的并发症将减少，这将是改善公共卫生的重要因素。