Ketones, Muscle Metabolism, and SGLT2 Inhibitors

酮、肌肉代谢和 SGLT2 抑制剂

• 批准号: 10595032
• 负责人: RALPH A DEFRONZO
• 金额: $ 64.73万
• 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/10595032
• 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; Oxygen; Pharmaceutical Preparations; 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; pharmacologic; 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.

项目总结/文摘