Ketones, Muscle Metabolism, and SGLT2 Inhibitors

酮、肌肉代谢和 SGLT2 抑制剂

• 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
• 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

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) 日益流行，美国约有 3600 万患者 仅凭这一点，就需要来自不同学科的科学家的积极参与。药品正在 开发用于管理葡萄糖代谢、调节胰岛素敏感性以及其他各种 T2DM 的病理生理因素。钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 最近被 旨在帮助管理血糖，并已被证明对代谢的各个组成部分有效 综合症。在 SGLT2i 试验中，心血管结局强调心力衰竭和心力衰竭的显着减少 减少患有心脏病的糖尿病患者的不良心脏事件。据研究推测 研究显示，与对照组相比，服用 SGLT2i 的糖尿病患者空腹酮浓度升高， 对代偿性酮代谢的偏好既由 SGLT2i 启动，又增强 心血管代谢性能。本提案的研究目标是开发定量 磁共振成像 (MRI) 和光谱学 (MRS) 功能可用于评估各种心脏疾病 磷代谢物和肌细胞内脂质的功能参数和体内测量 人体骨骼肌和心肌。这些研究将通过使用创建的协议来实施 幻影测试模型并在人类受试者中进行验证。目标 1. 使用心脏 MRI 和 1H-MRS 进行测量 心肌细胞内脂质含量和心包脂质体积的差异用于比较心血管 正常糖耐量受试者和 T2DM 受试者之间的表现。在目标 2 中，我们将使用 磷-31 MRS (31P-MRS) 和氢-1 (1H-MRS) 用于测量骨骼中代谢物浓度 正常葡萄糖耐量和 T2DM 受试者的肌肉。在目标 3 中，我们将开发 31P-MRS 来测量 心肌中的代谢物浓度，并结合 1H-MRS 评估心脏代谢物 正常耐糖受试者和 T2DM 受试者的浓度。