Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Eur J Endocrinol. 2024 Aug 5;191(2):192-203. doi: 10.1093/ejendo/lvae095.
Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D.
In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion.
Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]).
Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.
尽管二甲双胍被广泛用于治疗 2 型糖尿病（T2D），但其降血糖机制仍不清楚。使用胰高血糖素样肽 1（GLP-1）受体（GLP-1R）拮抗剂 exendin(9-39)NH2，我们检验了餐后 GLP-1 介导的作用有助于二甲双胍在 T2D 中降血糖潜力的假设。
在一项随机、安慰剂对照、双盲、交叉研究中，15 名 T2D 患者（中位 HbA1c 50 mmol/mol [6.7%]，体重指数 30.1 kg/m2，年龄 71 岁）分别接受 14 天的二甲双胍和安慰剂治疗，随机顺序进行。每个治疗期前进行 14 天无降血糖药物治疗，然后以随机顺序进行两次 4 小时混合餐测试，两次测试之间间隔>24 小时，并分别使用持续静脉输注 exendin(9-39)NH2 或生理盐水。
与安慰剂相比，二甲双胍治疗降低了空腹血糖（差异的平均值 [MD] 1.4 mmol/L × min [95%CI 0.8-2.0]）以及生理盐水输注期间的餐后血糖波动（MD 186 mmol/L × min [95%CI 64-307]）和 exendin(9-39)NH2 输注期间的餐后血糖波动（MD 268 mmol/L × min [95%CI 108-427]）。GLP-1R 拮抗作用对二甲双胍引起的餐后葡萄糖耐量改善没有影响（MD 82 mmol/L × min [95%CI -6564-170]）。二甲双胍治疗增加了空腹血浆 GLP-1（MD 1.7 pmol/L × min [95%CI 0.39-2.9]），但不影响餐后 GLP-1 反应（MD 820 pmol/L × min [95%CI -1750-111]）。
使用 GLP-1R 拮抗剂，我们无法在 T2D 患者中检测到二甲双胍的餐后 GLP-1 介导的降血糖作用。我们表明，2 周的二甲双胍治疗增加了空腹血浆 GLP-1，这可能有助于二甲双胍对 T2D 患者空腹血糖的有益作用。试验注册：Clinicaltrials.gov NCT03246451。
