二甲双胍诱导的胰高血糖素样肽-1 分泌有助于二甲双胍在 2 型糖尿病中的作用。
Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes.
机构信息
Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark.
Discipline of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, Australia.
出版信息
JCI Insight. 2018 Dec 6;3(23):93936. doi: 10.1172/jci.insight.93936.
BACKGROUND
Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes.
METHODS
Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity.
RESULTS
Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity.
CONCLUSIONS
Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action.
TRIAL REGISTRATION
NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074).
FUNDING
This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.
背景
二甲双胍可降低血糖水平，并已被证明可增加胰高血糖素样肽 1（GLP-1）的分泌。二甲双胍是否对 GLP-1 释放具有直接作用，以及二甲双胍的部分降血糖作用是否归因于 GLP-1 的释放，目前尚不清楚。本研究旨在调查二甲双胍诱导的 GLP-1 分泌及其对 2 型糖尿病患者二甲双胍整体降血糖作用的贡献及潜在机制。
方法
本研究纳入了 12 例 2 型糖尿病患者，采用安慰剂对照、双盲研究设计。在 4 天内，患者分别接受二甲双胍（1500mg）或安慰剂混悬于液体餐中，并随后静脉输注 GLP-1 受体拮抗剂 exendin9-39（Ex9-39）或生理盐水。在 240 分钟内采集血样。通过在有或没有 dorsomorphin 抑制 AMPK 活性的情况下，在人回肠和结肠组织中进行离体实验，测试二甲双胍对 GLP-1 分泌的直接作用。
结果
与安慰剂相比，二甲双胍增加了餐后 GLP-1 分泌（P=0.014），并且在接受二甲双胍+生理盐水治疗后，餐后血糖水平的升高明显低于接受二甲双胍+Ex9-39 治疗（P=0.004）。离体实验中，二甲双胍可迅速增加 GLP-1 分泌（结肠组织，P<0.01；回肠组织，P<0.05），但 AMPK 活性抑制后该作用被消除。
结论
二甲双胍对 GLP-1 分泌的 L 细胞具有直接且依赖 AMPK 的作用，可增加餐后 GLP-1 分泌，这似乎有助于二甲双胍的降血糖作用及其作用模式。
临床试验注册
NCT02050074（https://clinicaltrials.gov/ct2/show/NCT02050074）。
基金资助
本研究得到了 A.P. 穆勒基金会、诺和诺德基金会、丹麦医学协会研究基金、澳大利亚研究委员会、澳大利亚国家卫生与医学研究委员会以及辉瑞公司的资助。
Zotero 插件