二甲双胍降低2型糖尿病患者葡萄糖生成的机制。
Mechanism by which metformin reduces glucose production in type 2 diabetes.
作者信息
Hundal R S, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S E, Schumann W C, Petersen K F, Landau B R, Shulman G I
机构信息
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
出版信息
Diabetes. 2000 Dec;49(12):2063-9. doi: 10.2337/diabetes.49.12.2063.
To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.
为研究二甲双胍降低2型糖尿病患者内源性葡萄糖生成的机制，我们对7名2型糖尿病患者进行了研究，这些患者空腹血糖较高（15.5±1.3 mmol/l），在接受二甲双胍治疗3个月前后进行观察。选取7名年龄、性别和体重指数相匹配的健康受试者作为对照。通过13C核磁共振波谱法估算肝脏净糖原分解速率，并结合通过摄入2H2O中的2H标记血糖来测定糖异生和糖原分解对葡萄糖生成的贡献。使用[6,6-2H2]葡萄糖测量葡萄糖生成。糖尿病患者的葡萄糖生成速率是对照组的两倍（0.70±0.05 vs. 0.36±0.03 mmol·m(-2)·min(-1)，P<0.0001）。二甲双胍使该速率降低了24%（降至0.53±0.03 mmol·m(-2)·min(-1)，P = 0.0009），空腹血糖浓度降低了30%（降至10.8±0.9 mmol/l，P = 0.0002）。糖尿病患者的糖异生速率是对照组的三倍（0.59±0.03 vs. 0.18±0.03 mmol·m(-2)·min(-1)），二甲双胍使该速率降低了36%（降至0.38±0.03 mmol·m(-2)·min(-1)，P = 0.01）。通过2H2O法，糖尿病患者的糖异生速率增加了两倍（0.42±0.04 mmol·m(-2)·min(-1)），二甲双胍治疗后降低了33%（0.28±0.03 mmol·m(-2)·min(-1)，P = 0.0002）。对照组中不存在糖原循环，但在糖尿病患者中，糖原循环占葡萄糖生成的25%，这解释了两种方法结果存在差异的原因。总之，2型糖尿病控制不佳的患者内源性葡萄糖生成速率增加，这可归因于糖异生速率增加。二甲双胍通过降低糖异生降低了这些患者的葡萄糖生成速率。
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