Ketones, Muscle Metabolism, and SGLT2 Inhibitors

酮、肌肉代谢和 SGLT2 抑制剂

• 批准号: 10445180
• 负责人: RALPH A DEFRONZO
• 金额: $ 66.11万
• 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/10445180
• 关键词: Affect; Blood flow; Butyrates; Cardiovascular system; Deoxyglucose; Diabetes Mellitus; Disease; EFRAC; Fatty Acids; Glucose; Grant; Heart; Heart failure; Hospitalization; Individual; Infusion procedures; Ketones; Left; Lipolysis; Metabolic; Muscle; Myocardial; Myocardium; New York; Outcome; Oxides; Oxygen; Pharmaceutical Preparations; Pharmacology; Physiological; Placebos; Plasma; Positron-Emission Tomography; Protocols documentation; Risk; Skeletal Muscle; Type 2 diabetic; Ventricular; Water; acipimox; beta-Hydroxybutyrate; cardiac magnetic resonance imaging; design; diabetic patient; glucose uptake; heart metabolism; inhibitor; inhibitor therapy; mortality; muscle metabolism; skeletal; uptake

PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects 6.5 million individuals in the US (87). Diabetes and HF frequently occur together and each disorder increases the risk for the other. Recent trials (9-16) have demonstrated that SGLT2 inhibitors (SGLT2i) reduce hospitalization for heart failure and cardiovascular (CV) mortality. However, the mechanism(s) via which the SGLT2i benefit heart failure remain to be determined. Following SGLT2i therapy the plasma ketone concentration rises. Ketones are avidly taken up by the myocardium and, when oxidized, generate more ATP per molecule of oxygen compared to glucose and fatty acids. Therefore, the SGLT2i-induced rise in plasma ketones has been suggested to explain the drug’s beneficial effect on the heart. In Protocol I of the present grant we will examine in type 2 diabetic subjects with HF and reduced ejection fraction the effect of three infusion rates of beta-hydroxybutyrate (designed to span the physiologic and pharmacologic range of plasma ketone concentrations) on: (1) LV systolic and diastolic function using cardiac MRI; (2) myocardial blood flow with PET/15O-H2O; (3) myocardial glucose uptake with PET/18F-2-DOG ; (4) skeletal muscle glucose and ketone uptake. In Protocol II we will examine the effect of 3 months of dapagliflozin, an SGLT2i, versus placebo on: (1) LV systolic and diastolic function using cardiac MRI; (2) myocardial blood flow; (3) myocardial ketone uptake with PET/11C--OH-B, (4) skeletal muscle glucose and ketone uptake in type 2 diabetic subjects with HF and reduced ejection fraction. In Protocol III we examine whether inhibition of the dapagliflozin-induced rise in plasma ketone concentration with acipimox can block the beneficial effects of dapagliflozin on myocardial function and blood flow. Acipimox, an inhibitor of lipolysis, reduces the plasma ketone concentration to <0.02 mM and has no other known metabolic effects.

项目概要/摘要 美国有 650 万人患有心力衰竭 (HF) (87)。糖尿病和心力衰竭经常发生 在一起，每种疾病都会增加另一种疾病的风险。最近的试验（9-16）有 证明 SGLT2 抑制剂 (SGLT2i) 可以减少因心力衰竭而住院的情况，并且 心血管（CV）死亡率。然而，SGLT2i 使心脏受益的机制 失败仍有待确定。 SGLT2i 治疗后血浆酮浓度 上升。酮被心肌大量吸收，氧化后产生更多 ATP 与葡萄糖和脂肪酸相比，每分子氧的含量。因此，SGLT2i 引起的上升 有人建议用血浆中的酮来解释该药物对心脏的有益作用。在 目前拨款的第一方案，我们将在患有心力衰竭和减少的 2 型糖尿病受试者中进行检查 射血分数 β-羟基丁酸的三种输注速率的影响（旨在跨越 血浆酮浓度的生理和药理学范围）：（1）左心室收缩压和 使用心脏 MRI 检查舒张功能； (2)PET/15O-H2O心肌血流量； (3)心肌 PET/18F-2-DOG 的葡萄糖摄取； (4)骨骼肌葡萄糖和酮的摄取。在协议中 II 我们将检查 3 个月的达格列净（SGLT2i）与安慰剂相比对以下方面的影响：(1) LV 使用心脏 MRI 检查收缩和舒张功能； (2)心肌血流量； (3)心肌酮 PET/11C--OH-B 的摄取，(4) 2 型糖尿病患者骨骼肌葡萄糖和酮的摄取 患有心力衰竭和射血分数降低的受试者。在方案III中，我们检查是否抑制 达格列净引起的阿昔莫司血浆酮浓度升高可以阻断 达格列净对心肌功能和血流量的有益作用。阿昔莫司 (Acipimox) 抑制剂 脂肪分解，将血浆酮浓度降低至<0.02 mM，并且没有其他已知的 代谢影响。