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）：候选人以前的研究经验重点是研究医学成像的基本物理和技术进步，尤其是MRI物理学。由于候选人家族中糖尿病和痛苦的患病率不断增加，因此他已经对运用技术技能感兴趣，以调查2型糖尿病（T2DM）的发病机理。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，以使用成像方法将他定位为研究职业，以研究在胰岛素抵抗和糖尿病的情况下涉及线粒体功能障碍的过程。该培训的重点如下所述。胰岛素是葡萄糖代谢的重要调节剂，它通过刺激血液中的葡萄糖吸收并促进其作为肝脏和肌肉中的糖原储存来影响肝脏，肌肉和脂肪组织。当存在正常胰岛素水平时，葡萄糖异常低摄取是一种称为胰岛素耐药性（IR）的疾病。在瘦肉和肥胖的糖尿病患者中，骨骼肌中胰岛素耐药性的增加都是常见的。糖尿病中的葡萄糖水平升高会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是对糖尿病研究的强烈兴趣，研究人员正在研究一个整体理论框架以了解过程。这种类型的计算机建模将受益于直接从生计受试者组织中获得的细胞内代谢数据。非侵入性成像技术可以在一系列生理条件下测量代谢过程，从而可以对模型进行完善。这些数据将补充从切除的组织样品（包括透射电子显微镜和台式生物化学测定法）中获得的更多侵入性分析获得的信息。磷-31核磁共振光谱可用于证明胰岛素抵抗受试者的代谢受损。但是，需要对所使用的方法进行校准和优化，以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被广泛用于测量骨骼肌中的葡萄糖利用和组织血流。 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糖尿病患者的肌肉。希望这些工具能够提高人们对糖尿病发作的了解，并允许开发可以减轻与糖尿病相关的胰岛素耐药性疾病的疗法。

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