Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Medical Research Laboratory, Aarhus University Hospital, Aarhus, Denmark.
Cardiovasc Drugs Ther. 2021 Jun;35(3):491-503. doi: 10.1007/s10557-020-07050-5. Epub 2020 Aug 8.
The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism.
Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55-68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity.
Compared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, - 0.2%; 95% CI - 0.3 to 0.0; p = 0.03), reduced body weight (- 2.8 kg; 95% CI - 5.0 to - 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol L; 95% CI 0.4 to 6.0; p = 0.03). No changes were observed in whole-body insulin sensitivity, endogenous glucose production, and peripheral glucose disposal or oxidation with metformin. Equally, resting energy expenditure, lipid and urea turnover, and skeletal muscle mitochondrial respiratory capacity remained unaltered.
Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes.
URL: https://clinicaltrials.gov . Unique identifier: NCT02810132. Date of registration: June 22, 2016.
最近有研究表明，在患有慢性心力衰竭（HF）且无糖尿病的患者中，降糖药物二甲双胍可降低心肌耗氧量并提高心肌效率。然而，目前尚不清楚这些有益的心肌作用是否与二甲双胍诱导的全身胰岛素敏感性和底物代谢改变有关。
18 名射血分数降低且无糖尿病的 HF 患者（中位数年龄 65（四分位间距 55-68）；射血分数 39±6%；糖化血红蛋白 5.5 至 6.4%）被随机分为二甲双胍组（n=10）或安慰剂组（n=8），接受 3 个月的治疗。我们使用两步高胰岛素-正常血糖钳夹技术，结合葡萄糖、棕榈酸和尿素的同位素示踪剂，研究了二甲双胍对全身胰岛素敏感性的影响。通过间接热量测定法和高分辨率呼吸测定法测定了底物代谢和骨骼肌线粒体呼吸能力，并通过生物电阻抗分析评估了身体成分。主要观察指标是胰岛素敏感性的变化。
与安慰剂相比，二甲双胍治疗降低了平均糖化血红蛋白水平（绝对平均差异，-0.2%；95%CI-0.3 至 0.0；p=0.03），减轻了体重（-2.8kg；95%CI-5.0 至-0.6；p=0.02），并增加了空腹胰高血糖素水平（3.2pmol/L；95%CI0.4 至 6.0；p=0.03）。二甲双胍治疗并未观察到全身胰岛素敏感性、内源性葡萄糖产生以及外周葡萄糖摄取或氧化的变化。同样，静息能量消耗、脂质和尿素周转率以及骨骼肌线粒体呼吸能力也没有改变。
在无糖尿病的 HF 患者中，二甲双胍治疗时心肌效率的提高并非通过改善胰岛素作用介导的。
网址：https://clinicaltrials.gov。唯一标识符：NCT02810132。注册日期：2016 年 6 月 22 日。
