Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
Endocrinology. 2011 Dec;152(12):4610-9. doi: 10.1210/en.2011-1485. Epub 2011 Oct 4.
Glucagon-like peptide-1(7-36NH2) (GLP-1) is secreted by the intestinal L cell in response to both nutrient and neural stimulation, resulting in enhanced glucose-dependent insulin secretion. GLP-1 is therefore an attractive therapeutic for the treatment of type 2 diabetes. The antidiabetic drug, metformin, is known to increase circulating GLP-1 levels, although its mechanism of action is unknown. Direct effects of metformin (5-2000 μm) or another AMP kinase activator, aminoimidazole carboxamide ribonucleotide (100-1000 μm) on GLP-1 secretion were assessed in murine human NCI-H716, and rat FRIC L cells. Neither agent stimulated GLP-1 secretion in any model, despite increasing AMP kinase phosphorylation (P < 0.05-0.01). Treatment of rats with metformin (300 mg/kg, per os) or aminoimidazole carboxamide ribonucleotide (250 mg/kg, sc) increased plasma total GLP-1 over 2 h, reaching 37 ± 9 and 29 ± 9 pg/ml (P < 0.001), respectively, compared with basal (7 ± 1 pg/ml). Plasma activity of the GLP-1-degrading enzyme, dipeptidylpeptidase-IV, was not affected by metformin treatment. Pretreatment with the nonspecific muscarinic antagonist, atropine (1 mg/kg, iv), decreased metformin-induced GLP-1 secretion by 55 ± 11% (P < 0.05). Pretreatment with the muscarinic (M) 3 receptor antagonist, 1-1-dimethyl-4-diphenylacetoxypiperidinium iodide (500 μg/kg, iv), also decreased the GLP-1 area under curve, by 48 ± 8% (P < 0.05), whereas the antagonists pirenzepine (M1) and gallamine (M2) had no effect. Furthermore, chronic bilateral subdiaphragmatic vagotomy decreased basal secretion compared with sham-operated animals (7 ± 1 vs. 13 ± 1 pg/ml, P < 0.001) but did not alter the GLP-1 response to metformin. In contrast, pretreatment with the gastrin-releasing peptide antagonist, RC-3095 (100 μg/kg, sc), reduced the GLP-1 response to metformin, by 55 ± 6% (P < 0.01) at 30 min. These studies elucidate the mechanism underlying metformin-induced GLP-1 secretion and highlight the benefits of using metformin with dipeptidylpeptidase-IV inhibitors in patients with type 2 diabetes.
胰高血糖素样肽-1(7-36NH2)（GLP-1）是肠道 L 细胞在受到营养和神经刺激时分泌的，可促进葡萄糖依赖性胰岛素分泌。因此，GLP-1 是治疗 2 型糖尿病的一种有吸引力的治疗方法。二甲双胍是一种已知能增加循环 GLP-1 水平的抗糖尿病药物，但其作用机制尚不清楚。在鼠源性人 NCI-H716 和大鼠 FRIC L 细胞中评估了二甲双胍（5-2000μm）或另一种 AMP 激酶激活剂，氨基咪唑羧酰胺核苷酸（100-1000μm）对 GLP-1 分泌的直接作用。尽管增加了 AMP 激酶磷酸化（P<0.05-0.01），但这两种药物在任何模型中均未刺激 GLP-1 分泌。用二甲双胍（300mg/kg，口服）或氨基咪唑羧酰胺核苷酸（250mg/kg，sc）治疗大鼠可使血浆总 GLP-1 在 2 小时内增加 37±9 和 29±9pg/ml（P<0.001），分别与基础水平（7±1pg/ml）相比。二甲双胍治疗并未影响 GLP-1 降解酶二肽基肽酶-IV 的血浆活性。用非特异性毒蕈碱拮抗剂阿托品（1mg/kg，iv）预处理可使二甲双胍诱导的 GLP-1 分泌减少 55±11%（P<0.05）。用毒蕈碱（M）3 受体拮抗剂 1-1-二甲基-4-二苯乙氧基哌啶碘化物（500μg/kg，iv）预处理也可使 GLP-1 曲线下面积减少 48±8%（P<0.05），而拮抗剂哌仑西平和加兰他敏（M2）则没有影响。此外，慢性双侧膈下迷走神经切断术使基础分泌与假手术动物相比降低（7±1 与 13±1pg/ml，P<0.001），但不改变 GLP-1 对二甲双胍的反应。相反，用胃泌素释放肽拮抗剂 RC-3095（100μg/kg，sc）预处理可使 GLP-1 对二甲双胍的反应减少 55±6%（P<0.01），在 30 分钟时。这些研究阐明了二甲双胍诱导 GLP-1 分泌的机制，并强调了在 2 型糖尿病患者中使用二甲双胍和二肽基肽酶-IV 抑制剂的益处。
