Ketones, Muscle Metabolism, and SGLT2 Inhibitors

酮、肌肉代谢和 SGLT2 抑制剂

基本信息

批准号：
10632818
负责人：
RALPH A DEFRONZO
金额：
$ 3.62万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632818
关键词：
Adenosine Triphosphate Award Biochemical Process Blood Glucose Cardiac Cardiovascular system Clinical and Translational Science Awards Coupled Development Discipline Doctor of Philosophy Epidemic Evaluation Event Exercise Fasting Foundations Functional disorder Funding Glucagon Glucose Goals Grant Health Heart Heart Diseases Heart failure Human Hydrogen Image Imaging Techniques Individual Insulin Resistance Ketones Laboratories Lipids Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Mentors Metabolic Metabolic syndrome Metabolism Methods Modality Modeling Myocardial Myocardium National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Performance Pericardial body location Pharmaceutical Preparations Pharmacologic Substance Phosphocreatine Phosphorus Physics Physiological Processes Physiology Pioglitazone Protocols documentation Radiology Specialty Reproducibility Research Research Personnel Research Training Science Scientist Skeletal Muscle Sodium Solid Spectrum Analysis TNFSF15 gene Techniques Technology Testing Thiazolidinediones Training Triglycerides United States Work analytical tool cardiac magnetic resonance imaging diabetic diabetic cardiomyopathy exercise regimen fasting glucose glucose metabolism glucose tolerance heart function heart imaging heart metabolism human subject imaging biomarker improved in vivo inhibitor inhibitor therapy insulin regulation insulin sensitivity lipid metabolism metabolic abnormality assessment metabolic imaging muscle metabolism novel therapeutics phosphorus metabolism preference professor programs quantitative imaging receptor skeletal muscle metabolism spectroscopic imaging symporter

项目摘要

Abstract The growing epidemic of Type 2 Diabetes (T2DM), with approximately 36 million patients in the United States alone, requires the active engagement of scientists from a variety of disciplines. Pharmaceuticals are being developed for the management of glucose metabolism, regulation of insulin sensitivity, and various other pathophysiological factors of T2DM. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been recently developed to help manage blood sugar and have proven effective for various components of metabolic syndrome. In SGLT2i trials, cardiovascular outcomes emphasized a marked reduction of heart failure and decreases in adverse cardiac events in diabetics with prior heart disease. It is speculated, from studies showing elevated fasting ketone concentration in diabetics taking SGLT2i compared to controls, that a preference for a compensatory ketone metabolism is both kickstarted by SGLT2i’s and enhances cardiovascular metabolic performance. The goal of the research in this proposal is to develop quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) capabilities for the evaluation of various cardiac functional parameters and in-vivo measurement of phosphorus metabolites and intramyocellular lipids in human skeletal muscle and myocardium. These studies will be implemented through a protocol created using phantom test models and validated in human subjects. Aim 1. To use cardiac MRI and 1H-MRS to measure differences in intramyocellular lipids content and pericardial lipid volume for the comparison of cardiovascular performance between normal glucose tolerant subjects and subjects with T2DM. In Aim 2, we shall use phosphorus-31 MRS (31P-MRS) and hydrogen-1 (1H-MRS) to measure metabolite concentrations in skeletal muscle of normal glucose tolerant and T2DM subjects. In Aim 3, we shall develop 31P-MRS to measure metabolite concentrations in myocardium and to evaluate, in conjunction with 1H-MRS, cardiac metabolite concentrations in normal glucose tolerant subjects and subjects with T2DM.

抽象的 2型糖尿病（T2DM）的流行病日益增长，美国约有3600万患者单独需要从各个学科的科学家积极参与。制药正在存在开发用于管理葡萄糖代谢，胰岛素敏感性调节以及其他各种 T2DM的病理生理因素。钠 - 葡萄糖共转运蛋白2抑制剂（SGLT2I）已是开发以帮助管理血糖，并证明对代谢的各种组成部分有效综合征。在SGLT2I试验中，心血管结局强调了心力衰竭和患有先前心脏病的糖尿病患者的心脏事件会减少。从研究中推测与对照组相比偏爱补偿性酮代谢既由SGLT2I启动，又可以增强心血管代谢性能。该提案中研究的目的是开发定量磁共振成像（MRI）和光谱（MRS）能力，用于评估各种心脏磷代谢物的功能参数和体内测量人骨骼肌和心肌。这些研究将通过使用的协议来实施幻影测试模型，并在人类受试者中进行了验证。目的1。使用心脏MRI和1H-MR进行测量较大细胞内脂质含量和心包脂质体积的差异，以比较心血管正常的葡萄糖耐量受试者和T2DM受试者之间的性能。在AIM 2中，我们将使用磷-31 MRS（31p-MR）和氢-1（1H-MRS），以测量骨骼中的代谢产物浓度正常葡萄糖耐药和T2DM受试者的肌肉。在AIM 3中，我们将开发31p-Mrs以衡量心肌中的代谢产物浓度，并与1H-MRS，心脏代谢物评估正常葡萄糖耐受性受试者和T2DM受试者的浓度。