Journal Article

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects

Michael A. Nauck, Jens J. Holst, Juris J. Meier, Guido Kemmeries

2005

Overview

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects Juris J. Meier 1 2 , Guido Kemmeries 1 , Jens J. Holst 3 and Michael A. Nauck 1 4 1 Department of Medicine, Ruhr University, Bochum, Germany 2 Larry Hillblom Islet Research Center, UCLA School of Medicine, Los Angeles, California 3 Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark 4 Diabeteszentrum, Bad Lauterberg im Harz, Germany Address correspondence and reprint requests to Dr. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany. E-mail: m.nauck{at}diabeteszentrum.de Abstract 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. GIP, gastric inhibitory polypeptide GLP-1, glucagon-like peptide 1 Footnotes Accepted March 23, 2005. Received July 13, 2004. DIABETES

• Publisher: American Diabetes Association
• Subject: Adult / Amino acids / Biological and medical sciences / Blood Glucose - drug effects / Blood Glucose - metabolism / C-Peptide - blood / Cisapride / Cisapride - pharmacology / Diabetes / Diabetes. Impaired glucose tolerance / Domperidone - pharmacology / Drug dosages / Eating / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Erythromycin / Erythromycin - pharmacology / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Experiments / Gastric Emptying - drug effects / Gastric Emptying - physiology / Gastrointestinal motility / Gastrointestinal system / Glucagon / Glucagon - blood / Glucagon - pharmacokinetics / Glucagon - pharmacology / Glucagon-Like Peptide 1 / Glucose / Humans / Infusions, Intravenous / Insulin / Insulin - blood / Male / Medical sciences / Metoclopramide / Metoclopramide - pharmacology / Motility / Patient outcomes / Peptide Fragments - blood / Peptide Fragments - pharmacokinetics / Peptide Fragments - pharmacology / Placebos / Polypeptides / Protein Precursors - blood / Protein Precursors - pharmacokinetics / Protein Precursors - pharmacology / Reference Values