Investigation of the effect of oral metformin on dipeptidylpeptidase-4 (DPP-4) activity in Type 2 diabetes
Investigation of the effect of oral metformin on dipeptidylpeptidase-4 (DPP-4) activity in Type 2 diabetes
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DOI：
10.1111/j.1464-5491.2009.02748.x
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发表时间：
2009-06-01
影响因子：
3.5
通讯作者：
Bell, P. M.
中科院分区：
文献类型：
--
作者：
Cuthbertson, J.;Patterson, S.;Bell, P. M.
胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）是一种促胰岛素激素，是肠岛轴的主要成分。二肽基肽酶-4 （DPP-4）的快速降解和失活限制了其在人类糖尿病中的治疗潜力。我们研究了二甲双胍伴餐和不伴餐对2型糖尿病患者DPP-4活性的急性影响。在随机交叉设计中，10名2型糖尿病患者(6男4女，年龄65.8 +/- 2.6岁，体重指数30.0 +/- 1.2 kg/m（2)，糖化血红蛋白（HbA(1c)） 6.3 +/- 0.2%，平均+/- sem）口服二甲双胍1 g或安慰剂，同时服用标准混合餐（SMM）。6名受试者重新参加禁食，并接受1 g二甲双胍治疗，无SMM。SMM （n = 10）后，与安慰剂相比，二甲双胍未抑制DPP-4活性[曲线下面积（AUC）（0-4 h）分别为1574 +/- 4和1581 +/- 8 mu mol/ml/min]。血糖、胰岛素、GLP-1活性无显著差异。然而，与SMM相比，二甲双胍在禁食后抑制DPP-4活性（n = 6） （AUC(0-4 h) 1578 +/- 4比1494 +/- 9 mu mol/min， P < 0.02）。SMM后血清二甲双胍水平显著低于空腹（AUC(0-4 h) 350 +/- 66 vs 457 +/- 55 mg/ml/min） （P < 0.001）。二甲双胍在2型糖尿病患者空腹状态下抑制DPP-4活性，但与标准混合餐一起服用时无抑制作用。如果与食物一起服用，二甲双胍的血清浓度会降低。在确定如何使药物的功效最大化时应考虑到这些发现。
Glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone and major component of the enteroinsular axis. Its therapeutic potential in human diabetes is limited by rapid degradation and inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4). We investigated the acute effects of metformin with and without food on DPP-4 activity in Type 2 diabetes.Ten subjects with Type 2 diabetes (6 male/4 female, age 65.8 +/- 2.6 years, body mass index 30.0 +/- 1.2 kg/m(2), glycated haemoglobin (HbA(1c)) 6.3 +/- 0.2%, mean +/- sem) received metformin 1 g orally or placebo together with a standard mixed meal (SMM) in a random crossover design. Six subjects re-attended fasting and received metformin 1 g without a SMM.Following SMM (n = 10), DPP-4 activity was not suppressed by metformin compared with placebo [area under curve (AUC)(0-4 h) 1574 +/- 4 vs. 1581 +/- 8 mu mol/ml/min, respectively]. Plasma glucose, insulin and active GLP-1 were not different. However, DPP-4 activity was suppressed with metformin following fasting compared with a SMM (n = 6) (AUC(0-4 h) 1578 +/- 4 vs. 1494 +/- 9 mu mol/min, P < 0.02). Metformin serum levels were significantly lower (P < 0.001) after SMM than fasting (AUC(0-4 h) 350 +/- 66 vs. 457 +/- 55 mg/ml/min).Metformin inhibits DPP-4 activity in Type 2 diabetic patients in the fasting state but not when taken with a standard mixed meal. Metformin serum concentrations are lower if the drug is taken with food. These findings should be taken into account in establishing how to maximize efficacy of the drug.