Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects
Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects
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DOI：
10.2337/diabetes.54.7.2212
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发表时间：
2005-07-01
期刊：
影响因子：
7.7
通讯作者：
Nauck, MA
中科院分区：
文献类型：
--
作者：
Meier, JJ;Kemmeries, G;Nauck, MA
胰高血糖素样肽 1 (GLP-1) 由于能够增强葡萄糖刺激的胰岛素分泌而被认为可充当肠促胰岛素激素。由于 GLP-1 也会减缓胃排空，因此它在生理上会减少而不是增强餐后胰岛素分泌反应。因此，我们旨在通过GLP-1对抗胃排空减慢来研究其对餐后胰岛素分泌的影响。九名健康男性志愿者（年龄 25 +/- 4 岁，BMI 25.0 +/- 4.9 kg/m(2)）接受了 GLP-1（0.8 pmol (.) kg(-1) (.) min(-1)，-30 至 240 分钟）或安慰剂输注的研究。在不同的场合，除了 GLP-1 之外，还给予促动力药物甲氧氯普胺（10 mg）、多潘立酮（10 mg）、西沙必利（10 mg，每次口服 -30 分钟）或红霉素（200 mg 静脉注射，-30 至 -15 分钟）。 0 分钟时给予液体测试餐（50 g 蔗糖和 8% 混合氨基酸，400 ml）。抽取毛细血管和静脉血样本，测定葡萄糖（葡萄糖氧化酶）、胰岛素、C 肽、GLP-1、胰高血糖素、抑胃多肽 (GIP) 和胰多肽（特异性免疫测定）。通过酚红稀释技术评估胃排空。使用重复测量方差分析和邓肯事后检验进行统计分析。 GLP-1 显着减慢胃排空速度 (P < 0.001)。红霉素完全抵消了这一作用，而使用的其他促动力药物则没有效果。 GLP-1 降低了餐后血糖浓度（与安慰剂相比，P < 0.001），但红霉素部分逆转了这种作用（P < 0.05）。 GLP-1 给药期间，对膳食的胰岛素分泌反应较低（与安慰剂相比，P < 0.05）。然而，当红霉素添加到 GLP-1 中时，胰岛素浓度与安慰剂实验中的相似。 GLP-1 对进餐相关的胰高血糖素分泌增加的抑制作用被红霉素逆转（P < 0.001）。 GLP-1给药期间GIP分泌的时程被延迟（P < 0.05），但当添加红霉素时，该模式与安慰剂实验相似。 GLP-1 给药导致胰多肽血浆浓度降低（P < 0.05）。相反，红霉素显着增加胰多肽水平（P < 0.001）。静脉注射红霉素可能通过与副交感神经系统（胰多肽反应）相互作用来抵消 GLP-1 引起的胃排空减慢。尽管胰岛素分泌增加，但当胃排空减慢受到拮抗时，GLP-1 的降血糖作用显着降低，这说明了 GLP-1 多种抗糖尿病作用的这一方面的重要性。
Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 +/- 4 years, BMI 25.0 +/- 4.9 kg/m(2)) were studied with an infusion of GLP-1 (0.8 pmol (.) kg(-1) (.) min(-1) from -30 to 240 min) or placebo. On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at -30 min per oral), or erythromycin (200 mg intravenously from -30 to -15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan's post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying (P < 0.001). This was completely counterbalanced by erythromycin, whereas the other prokinetic drugs used had no effect. Postprandial glucose concentrations were lowered by GLP-1 (P < 0.001 vs. placebo), but this effect was partially reversed by erythromycin (P < 0.05). Insulin secretory responses to the meal were lower during GLP-1 administration (P < 0.05 vs. placebo). However, when erythromycin was added to GLP-1, insulin concentrations were similar to those in placebo experiments. The suppression of meal-related increments in glucagon secretion by GLP-1 was reversed by erythromycin (P < 0.001). The time course of GIP secretion was delayed during GLP-1 administration (P < 0.05), but when erythromycin was added, the pattern was similar to placebo experiments. GLP-1 administration led to a reduction in pancreatic polypeptide plasma concentrations (P < 0.05). In contrast, pancreatic polypeptide levels were markedly increased by erythromycin (P < 0.001). Intravenous erythromycin counteracts the deceleration of gastric emptying caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1.