Imaging Biomarkers for Evaluating Mitochondrial Function in Diabetes

用于评估糖尿病线粒体功能的成像生物标志物

• 批准号: 8537145
• 负责人: GEOFFREY DAVID CLARKE
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537145
• 关键词: Adenosine Triphosphate; Affect; Area; Back; Biochemical; Biochemical Process; Biochemistry; Biological Assay; Biological Markers; Biology; Blood; Blood Glucose; Blood flow; Characteristics; Chemicals; Clinical; Clinical Medicine; Clinical Research; Complement; Computer Simulation; Concentration measurement; Creatine; Creatine Kinase; Data; Deoxyglucose; Development; Diabetes Mellitus; Energy-Generating Resources; Exercise; Family; Fatty acid glycerol esters; Fluorine; Functional disorder; Future; Generations; Glucose; Glycogen; Goals; Human; Hydrogen; Hyperglycemia; Image; Imaging Techniques; Imaging technology; Insulin; Insulin Resistance; Kinetics; Knowledge; Laboratory Research; Lead; Liver; Magnetic Resonance Imaging; Measurement; Measures; Medical Imaging; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Models; Muscle; Myocardium; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Outcome; Oxygen; Pathogenesis; Patients; Perfusion; Phosphocreatine; Phosphorus; Physics; Physiological; Plasma; Positioning Attribute; Positron-Emission Tomography; Prevalence; Process; Production; Reaction; Reactive Oxygen Species; Recovery; Research; Research Personnel; Research Training; Resistance; Rest; Skeletal Muscle; Syndrome; Testing; Tissue Sample; Tissues; Training; Transmission Electron Microscopy; Water; Work; career; density; design; diabetic; diabetic patient; experience; fatty acid oxidation; feeding; glucose metabolism; glucose uptake; imaging modality; improved; in vivo; inorganic phosphate; interest; magnetic field; magnetic resonance spectroscopic imaging; minimally invasive; mitochondrial dysfunction; molecular modeling; muscle metabolism; oxidation; reaction rate; response; skills; therapy development; tool

DESCRIPTION (provided by applicant): The candidate's previous research experience has focused on studying the basic physics and technological advances of medical imaging, particularly MRI physics. Due to the increasing prevalence of diabetes and afflictions in the own candidate's family, he has become interested in applying his technical skills to investigate the pathogenesis of type 2 diabetes mellitus (T2DM). The overall goal of this proposal is to expand the candidate's training and practical experience in areas of metabolic biology and clinical medicine to position him for a research career using imaging methods to study the processes involved in mitochondrial dysfunction in the setting of insulin resistance and diabetes. The focus of this training is described below. Insulin is an important regulator of glucose metabolism that affects liver, muscle and fat tissue by stimulating glucose uptake from blood and promoting its storage as glycogen in liver and muscle. Abnormally low uptake of glucose, when there are normal insulin levels, is a condition known as insulin resistance (IR). Increased insulin resistance in skeletal muscle is common in both lean and obese diabetic subjects. The increased glucose levels in diabetes lead to production of reactive oxygen species in mitochondria, which probably impairs the ability of mitochondria to produce adequate energy in insulin resistance. The action of insulin resistance in skeletal muscle metabolism is of intense interest in diabetes research and investigators are working on an overall theoretical framework to understand the processes. This type of computer modeling would benefit from intracellular metabolic data acquired directly from the tissues of livings subjects. Noninvasive imaging technologies can measure metabolic processes under a range of physiological conditions, allowing refinement of the models. These data would supplement information obtained from more invasive analyses from excised tissue samples, including transmission electron microscopy and bench top biochemical assays. Phosphorus-31 nuclear magnetic resonance spectroscopy can be used to demonstrate impaired metabolism in subjects with insulin resistance. However the methods used need to be calibrated and optimized to supply highly accurate information for physiological models. Also, positron emission tomography has been used extensively to measure glucose utilization and tissue blood flow in skeletal muscle. The overall goals of the proposed project are to develop these imaging methods to measure the concentrations of various chemicals in skeletal muscle that are important intermediaries of metabolism, measure the rate at which important reactions progress, measure muscle blood flow and measure glucose utilization rate, while the blood glucose level is being strictly controlled in order to develop and refine computer models of molecular and biochemical mechanisms that contribute to insulin resistance in the skeletal muscle of diabetic patients. It is hoped that these tools will lead to improved understanding of the onset of diabetes and allow development of therapies that can alleviate the insulin resistant condition associated with diabetes.

描述（由申请人提供）：候选人之前的研究经验主要集中于研究医学成像的基础物理和技术进步，特别是 MRI 物理。由于候选人家庭中糖尿病的患病率和疾病不断增加，他开始有兴趣运用自己的技术技能来研究 2 型糖尿病 (T2DM) 的发病机制。该提案的总体目标是扩大候选人在代谢生物学和临床医学领域的培训和实践经验，使他能够从事利用成像方法研究胰岛素抵抗和糖尿病背景下线粒体功能障碍的过程的研究生涯。现将本次培训的重点介绍如下。胰岛素是葡萄糖代谢的重要调节剂，通过刺激血液中葡萄糖的摄取并促进其在肝脏和肌肉中以糖原的形式储存来影响肝脏、肌肉和脂肪组织。当胰岛素水平正常时，葡萄糖摄入量异常低，这种情况称为胰岛素抵抗 (IR)。骨骼肌胰岛素抵抗增加在瘦和肥胖糖尿病受试者中都很常见。糖尿病中葡萄糖水平升高导致线粒体中活性氧的产生，这可能会损害线粒体在胰岛素抵抗中产生足够能量的能力。胰岛素抵抗在骨骼肌代谢中的作用引起了糖尿病研究的浓厚兴趣，研究人员正在研究一个整体的理论框架来理解这一过程。这种类型的计算机建模将受益于直接从生物体组织获取的细胞内代谢数据。无创成像技术可以测量一系列生理条件下的代谢过程，从而可以完善模型。这些数据将补充从切除的组织样本进行更具侵入性的分析中获得的信息，包括透射电子显微镜和台式生化测定。 Phosphor-31 核磁共振波谱可用于证明胰岛素抵抗受试者的代谢受损。然而，所使用的方法需要进行校准和优化，以便为生理模型提供高度准确的信息。此外，正电子发射断层扫描已广泛用于测量骨骼肌中的葡萄糖利用率和组织血流量。该项目的总体目标是开发这些成像方法来测量骨骼肌中各种化学物质的浓度，这些化学物质是新陈代谢的重要中介，测量重要反应进展的速率，测量肌肉血流量并测量葡萄糖利用率，同时严格控制血糖水平，以开发和完善导致糖尿病患者骨骼肌胰岛素抵抗的分子和生化机制的计算机模型。希望这些工具能够增进对糖尿病发病的了解，并开发出能够缓解与糖尿病相关的胰岛素抵抗病症的疗法。

项目成果

Reduced skeletal muscle phosphocreatine concentration in type 2 diabetic patients: a quantitative image-based phosphorus-31 MR spectroscopy study.

• DOI: 10.1152/ajpendo.00426.2017
• 发表时间: 2018-08
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: E. Ripley;G. Clarke;Vala Hamidi;Robert A. Martinez;F. Settles;C. Solis;Shengwen Deng;M. Abdul-Ghani-M.-A

Fiber orientation measurements by diffusion tensor imaging improve hydrogen-1 magnetic resonance spectroscopy of intramyocellular lipids in human leg muscles.

通过扩散张量成像进行的纤维取向测量改善了人类腿部肌肉中肌细胞内脂质的氢 1 磁共振波谱。

• DOI: 10.1117/1.jmi.2.2.026002
• 发表时间: 2015
• 期刊: Journal of medical imaging (Bellingham, Wash.)
• 作者: Valaparla,SunilK;Gao,Feng;Daniele,Giuseppe;Abdul-Ghani,Muhammad;Clarke,GeoffreyD
• 通讯作者: Clarke,GeoffreyD

Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes.

• DOI: 10.2337/dc17-0078
• 发表时间: 2017-11
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Clarke GD;Solis-Herrera C;Molina-Wilkins M;Martinez S;Merovci A;Cersosimo E;Chilton RJ;Iozzo P;Gastaldelli A;Abdul-Ghani M;DeFronzo RA
• 通讯作者: DeFronzo RA