Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich J E
University of Rochester School of Medicine, New York 14642, USA.
N Engl J Med. 1995 Aug 31;333(9):550-4. doi: 10.1056/NEJM199508313330903.
The metabolic effects and mechanism of action of metformin are still poorly understood, despite the fact that it has been used to treat patients with non-insulin-dependent diabetes mellitus (NIDDM) for more than 30 years.
In 10 obese patients with NIDDM, we used a combination of isotope dilution, indirect calorimetry, bioimpedance, and tissue-balance techniques to assess the effects of metformin on systemic lactate, glucose, and free-fatty-acid turnover; lactate oxidation and the conversion of lactate to glucose; skeletal-muscle glucose and lactate metabolism; body composition; and energy expenditure before and after four months of treatment.
Metformin treatment decreased the mean (+/- SD) glycosylated hemoglobin value from 13.2 +/- 2.2 percent to 10.5 +/- 1.6 percent (P < 0.001) and reduced fasting plasma glucose concentrations from 220 +/- 41 to 155 +/- 28 mg per deciliter (12.2 +/- 0.7 to 8.6 +/- 0.5 mmol per liter) (P < 0.001). Although resting energy expenditure did not change, the patients lost 2.7 +/- 1.3 kg of weight (P < 0.001), 88 percent of which was adipose tissue. The mean (+/- SE) rate of plasma glucose turnover (hepatic glucose output and systemic glucose disposal) decreased from 2.8 +/- 0.2 to 2.0 +/- 0.2 mg per kilogram of body weight per minute (15.3 +/- 0.9 to 10.8 +/- 0.9 mumol per kilogram per minute) (P < 0.001), as a result of a decrease in hepatic glucose output; systemic glucose clearance did not change. The rate of conversion of lactate to glucose (gluconeogenesis) decreased by 37 percent (P < 0.001), whereas lactate oxidation increased by 25 percent (P < 0.001). There were no changes in the plasma lactate concentration, plasma lactate turnover, muscle lactate release, plasma free-fatty-acid turnover, or uptake of glucose by muscle.
Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis. It also seems to induce weight loss, preferentially involving adipose tissue.
尽管二甲双胍已用于治疗非胰岛素依赖型糖尿病（NIDDM）患者超过30年，但其代谢效应及作用机制仍未完全明确。
我们对10名肥胖的NIDDM患者，采用同位素稀释、间接测热法、生物电阻抗和组织平衡技术相结合的方法，评估治疗四个月前后二甲双胍对全身乳酸、葡萄糖和游离脂肪酸周转；乳酸氧化及乳酸向葡萄糖的转化；骨骼肌葡萄糖和乳酸代谢；身体组成以及能量消耗的影响。
二甲双胍治疗使糖化血红蛋白平均值（±标准差）从13.2±2.2%降至10.5±1.6%（P<0.001），空腹血糖浓度从220±41降至155±28毫克/分升（12.2±0.7至8.6±0.5毫摩尔/升）（P<0.001）。虽然静息能量消耗未改变，但患者体重减轻了2.7±1.3千克（P<0.001），其中88%为脂肪组织。由于肝脏葡萄糖输出减少，血浆葡萄糖周转平均速率（±标准误）（肝脏葡萄糖输出和全身葡萄糖处置）从2.8±0.2降至2.0±0.2毫克/千克体重/分钟（15.3±0.9至10.8±0.9微摩尔/千克/分钟）（P<0.001），全身葡萄糖清除率未改变。乳酸向葡萄糖的转化速率（糖异生）降低了37%（P<0.001），而乳酸氧化增加了25%（P<0.001）。血浆乳酸浓度、血浆乳酸周转、肌肉乳酸释放、血浆游离脂肪酸周转或肌肉对葡萄糖的摄取均无变化。
二甲双胍主要通过降低肝脏葡萄糖输出发挥作用，主要是通过抑制糖异生。它似乎还能导致体重减轻，优先减少脂肪组织。
