Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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]).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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]).
CONCLUSIONS: 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.
摘要：
目的：虽然二甲双胍广泛用于治疗2型糖尿病（T2D），其降糖机制尚不清楚.使用胰高血糖素样肽1（GLP-1）受体（GLP-1R）拮抗剂exendin（9-39）NH2，我们测试了餐后GLP-1介导的作用有助于二甲双胍在T2D中的降糖潜力的假设。
方法：在随机的，安慰剂对照,双盲,交叉研究，15例T2D患者（HbA1c中位数为50mmol/mol（6.7％），BMI30.1kg/m2，年龄71岁）接受，按随机顺序，二甲双胍和安慰剂治疗14天，分别。每个治疗期之前为14天，没有任何降糖药物，并通过以随机顺序进行的两次4小时混合餐测试结束，并以>24小时的间隔连续静脉注射exendin（9-39）NH2或盐水输注。
结果：与安慰剂相比，二甲双胍治疗可降低空腹血糖（平均差异（MD）1.4mmol/l×min（95％CI0.8-2.0））以及盐水输注（MD186mmol/l×min（95％CI64-307））和exendin（9-39）NH2输注（MD268mmol/l×min（95％CI108-427））。二甲双胍诱导的餐后葡萄糖耐量改善不受GLP-1R拮抗作用的影响（MD82mmol/l×min（95％CI-6,564-170））。二甲双胍治疗可增加空腹血浆GLP-1（MD1.7pmol/l×min（95％CI0.39-2.9）），但不影响餐后GLP-1反应（MD820pmol/l×min（95％CI-1,750-111））。
结论：使用GLP-1R拮抗，我们无法检测到GLP-1介导的二甲双胍在T2D患者中的餐后降糖作用.我们显示，二甲双胍治疗两周可增加空腹血浆GLP-1，这可能有助于二甲双胍对T2D空腹血糖的有益作用。
背景：Clinicaltrials.govNCT03246451。
方法：在随机的，安慰剂对照,双盲,交叉研究，15例T2D患者（HbA1c中位数为50mmol/mol（6.7％），BMI30.1kg/m2，年龄71岁）接受，按随机顺序，二甲双胍和安慰剂治疗14天，分别。每个治疗期之前为14天，没有任何降糖药物，并通过以随机顺序进行的两次4小时混合餐测试结束，并以>24小时的间隔连续静脉注射exendin（9-39）NH2或盐水输注。
结果：与安慰剂相比，二甲双胍治疗可降低空腹血糖（平均差异（MD）1.4mmol/l×min（95％CI0.8-2.0））以及盐水输注（MD186mmol/l×min（95％CI64-307））和exendin（9-39）NH2输注（MD268mmol/l×min（95％CI108-427））。二甲双胍诱导的餐后葡萄糖耐量改善不受GLP-1R拮抗作用的影响（MD82mmol/l×min（95％CI-6,564-170））。二甲双胍治疗可增加空腹血浆GLP-1（MD1.7pmol/l×min（95％CI0.39-2.9）），但不影响餐后GLP-1反应（MD820pmol/l×min（95％CI-1,750-111））。
结论：使用GLP-1R拮抗，我们无法检测到GLP-1介导的二甲双胍在T2D患者中的餐后降糖作用.我们显示，二甲双胍治疗两周可增加空腹血浆GLP-1，这可能有助于二甲双胍对T2D空腹血糖的有益作用。
背景：Clinicaltrials.govNCT03246451。
