Ketones, Muscle Metabolism, and SGLT2 Inhibitors

项目摘要/摘要 心力衰竭(HF)影响着美国650万人(87人)。糖尿病和心力衰竭频繁发生 在一起，每一种疾病都会增加另一种疾病的风险。最近的试验(9-16) 证明SGLT2抑制剂(SGLT2i)减少了心力衰竭的住院时间和 心血管(CV)死亡率。然而，SGLT2i有益心脏的机制(S) 失败还有待确定。SGLT2i治疗后血酮浓度的变化 升起。酮被心肌贪婪地摄取，并在氧化时产生更多的三磷酸腺苷 与葡萄糖和脂肪酸相比，每分子氧。因此，SGLT2i诱导的上升 在血浆中，酮被建议用来解释这种药物对心脏的有益作用。在……里面 本资助的方案一，我们将检查患有心力衰竭和减少的2型糖尿病患者。 射血分数：三种不同输注速率的β-羟丁酸(设计跨越 血酮浓度的生理和药理范围)对：(1)左心室收缩压和 心脏MRI的舒张期功能；(2)PET/15O-H2O的心肌血流量；(3)心肌 PET/18F-2-DOG摄取葡萄糖；(4)骨骼肌葡萄糖摄取和酮体摄取。在协议中 我们将检验达格列酮(一种SGLT2i)与安慰剂3个月对：(1)LV的影响。 心脏MRI的收缩和舒张期功能；(2)心肌血流量；(3)心肌酮 PET/11C--OH-B摄取，(4)2型糖尿病患者骨骼肌葡萄糖和酮体摄取 受试者心力衰竭且射血分数降低。在第三号议定书中，我们审查了是否禁止 阿昔莫司可阻断达帕利秦引起的血酮浓度升高。 达帕格列酮对心肌功能和血流量的有益影响。阿昔莫司，阿昔洛韦的抑制剂 脂肪分解，将血浆酮浓度降低到0.02 mM，没有其他已知的 新陈代谢影响。

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.