Ketones, Muscle Metabolism, and SGLT2 Inhibitors

摘要 2型糖尿病（T2 DM）的流行日益严重，美国约有3600万患者 这本身就需要来自不同学科的科学家的积极参与。制药业正在 开发用于管理葡萄糖代谢、调节胰岛素敏感性和各种其他 2型糖尿病的病理生理因素。钠-葡萄糖协同转运蛋白2抑制剂（SGLT 2 i）最近已被 开发，以帮助管理血糖，并已被证明有效的各种成分的代谢 综合征在SGLT 2 i试验中，心血管结局强调心力衰竭显著减少， 降低有心脏病史的糖尿病患者的不良心脏事件。据推测，根据研究， 显示与对照组相比，服用SGLT 2 i的糖尿病患者空腹血酮浓度升高， 对代偿性酮代谢的偏好是由SGLT 2 i启动的，并增强 心血管代谢性能。本研究的目标是开发定量的 磁共振成像（MRI）和波谱（MRS）功能，用于评估各种心脏 磷代谢物和肌细胞内脂质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 体模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测量 心肌细胞内脂质含量和心包脂质体积的差异， 正常葡萄糖耐量受试者和T2 DM受试者之间的性能。在目标2中，我们将使用 磷-31 MRS（31 P-MRS）和氢-1（1H-MRS），以测量骨骼中的代谢物浓度 正常葡萄糖耐受和T2 DM受试者的肌肉。在目标3中，我们将开发31 P-MRS来测量 心肌代谢物浓度，并结合1H-MRS评价心脏代谢物 正常葡萄糖耐受受试者和T2 DM受试者中的浓度。

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.