Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen N, Denmark.
Diabetologia. 2012 Feb;55(2):443-9. doi: 10.1007/s00125-011-2340-0. Epub 2011 Oct 19.
AIMS/HYPOTHESIS: The glucose-lowering drug metformin has been shown to inhibit complex I of the mitochondrial electron transport chain in skeletal muscle. To investigate this effect in vivo we studied skeletal muscle mitochondrial respiratory capacity and content from patients with type 2 diabetes treated with metformin (n = 14) or sulfonylurea (n = 8) and healthy control (n = 18) participants.
Mitochondrial respiratory capacity was measured ex vivo in permeabilised muscle fibres obtained from the vastus lateralis muscle of all participants. The respiratory response to in vitro titration with metformin was measured in controls. Citrate synthase (CS) activity, and fasting plasma glucose, insulin and HbA(1c) levels were measured and body composition was determined.
Participants were matched for age, BMI and percentage body fat. Fasting plasma glucose concentrations were higher (p < 0.05) in those treated with sulfonylureas and metformin than in controls. CS activity was comparable between metformin-treated and control participants, but tended to be lower in those receiving sulfonylureas. Mitochondrial respiratory capacity with substrates for complex I and complex I and II was comparable in the groups, both when estimated per mg of tissue and when normalised to CS activity. In vitro metformin titration demonstrated a dose-dependent inhibitory effect on complex I and II in human skeletal muscle at suprapharmacological concentrations.
CONCLUSIONS/INTERPRETATION: Metformin treatment does not inhibit mitochondrial complex I respiration in the electron transport chain in human skeletal muscle of patients with type 2 diabetes when measured ex vivo. Inhibition of complex I and II respiration in controls was demonstrated by metformin titration in vitro at doses well above those observed during metformin treatment.
目的/假设：降血糖药物二甲双胍已被证明可抑制骨骼肌中线粒体电子传递链的复合物 I。为了在体内研究这种作用，我们研究了接受二甲双胍（n = 14）或磺酰脲（n = 8）治疗的 2 型糖尿病患者以及健康对照（n = 18）参与者的骨骼肌线粒体呼吸能力和含量。
我们在所有参与者的股外侧肌中获得的透化肌纤维中离体测量线粒体呼吸能力。在对照中测量了体外与二甲双胍滴定的呼吸反应。测量了柠檬酸合酶（CS）活性、空腹血糖、胰岛素和 HbA（1c）水平，并确定了身体成分。
参与者在年龄、BMI 和体脂百分比方面相匹配。磺酰脲类和二甲双胍治疗者的空腹血糖浓度高于对照组（p < 0.05）。CS 活性在接受二甲双胍治疗和对照组参与者之间相当，但在接受磺酰脲类治疗者中趋于较低。以组织每毫克计和以 CS 活性标准化时，I 型和 I 型和 II 型底物的线粒体呼吸能力在各组之间是可比的。在体外二甲双胍滴定中，在药理浓度以上，在人类骨骼肌中观察到对复合物 I 和 II 的剂量依赖性抑制作用。
结论/解释：当在体外测量时，二甲双胍治疗不会抑制 2 型糖尿病患者骨骼肌中线粒体电子传递链的复合物 I 呼吸。在体外通过二甲双胍滴定在远高于二甲双胍治疗期间观察到的剂量下，证明了对复合物 I 和 II 呼吸的抑制。
