Aims/hypothesis

Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes.

Methods

Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = −60, −30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0–60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = −60 min and t = 120 min.

Results

There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = −60 or −30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = −60 or −30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given.

Conclusions/interpretation

In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control.

Trial registration

www.anzctr.org.au ACTRN12621000878875

Funding

The study was not funded by a specific research grant.

Graphical Abstract

中文翻译：

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二甲双胍给药时机对 2 型糖尿病十二指肠内葡萄糖输注的血糖和胰高血糖素样肽 1 反应的影响：双盲、随机、安慰剂对照、交叉研究

目标/假设

二甲双胍通过调节胃肠道功能，包括刺激胰高血糖素样肽-1 (GLP-1)，降低 2 型糖尿病患者的餐后血糖波动。改变二甲双胍给药时间对餐后葡萄糖代谢的影响尚不清楚。我们评估了在十二指肠内葡萄糖输注之前以不同时间间隔给药的二甲双胍对二甲双胍治疗的 2 型糖尿病患者随后的血糖、胰岛素和 GLP-1 反应的影响。

方法

采用交叉设计，在不同的四天内对 16 名通过二甲双胍单一疗法控制相对较好的 2 型糖尿病参与者进行了研究。每天，参与者被随机分配在t = -60、-30 或 0 分钟时通过鼻十二指肠导管推注二甲双胍（1000 毫克溶于 50 毫升 0.9% 盐水）（在其他时间点接受盐水）或在所有时间点（对照），然后在t = 0–60 分钟时十二指肠内葡萄糖输注 12.56 kJ/min (3 kcal/min) 。这些治疗对参与研究程序的参与者和研究人员都是不知情的。在t = -60 分钟和t = 120 分钟之间每 30 分钟测量一次血浆葡萄糖、胰岛素和总 GLP-1 水平。

结果

二甲双胍在降低血浆葡萄糖水平和增加血浆 GLP-1 和胰岛素水平方面存在随时间治疗的相互作用（均p <0.05）。与t = 0 分钟相比，在t = -60 或 -30分钟时给予二甲双胍时，血浆葡萄糖水平的降低更大（每个p <0.05），并且血浆 GLP-1 水平的增加仅在给予二甲双胍时才明显t = −60或 −30 分钟（每个p <0.05）。尽管二甲双胍不影响胰岛素敏感性，但它增强了葡萄糖诱导的胰岛素分泌（p <0.05），并且血浆胰岛素水平的增加与给予二甲双胍的第3天相当。

结论/解释

对于控制良好的二甲双胍治疗的 2 型糖尿病，二甲双胍在肠内葡萄糖给药前给药时比与肠内葡萄糖同时给药时，其降血糖作用更大，并且这与更强的 GLP-1 反应相关。这些观察结果表明，饭前服用二甲双胍可以优化其改善餐后血糖控制的效果。

试用注册

www.anzctr.org.au ACTRN12621000878875

资金

该研究没有得到特定研究补助金的资助。

图形概要