Glucagon-like peptide 2 inhibits ghrelin secretion in humans
Introduction
The 28 amino acid hormone ghrelin is secreted from Gr-cells in the stomach and acts as an endogenous growth hormone secretagogue receptor ligand [1], [2], [3]. There is an emerging evidence that ghrelin plays an important role in the neuro-endocrine control of food intake and energy homeostasis [4], [5]. Along these lines, ghrelin induces hunger and stimulates food intake in rodents and humans even after peripheral administration [4], [5], [6], [7], [8], [9], [10]. Furthermore, the peptide has been suggested to accelerate gastric emptying and to stimulate gastric acid secretion through activation of the vagal nervous system [11]. Circulating ghrelin levels are high under fasting conditions, and sharply decline after meal ingestion [12], [13]. As yet, the mechanisms underlying the postprandial drop in ghrelin levels are poorly understood, but conceivably the secretion of gastrointestinal hormones, such as gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1) or glucagon-like peptide 2 (GLP-2) might be involved [14], [15]. Previous studies examining the role of GIP and GLP-1 in this process have been conflicting. Thus, in isolated rat stomach preparations GLP-1 was shown to decrease ghrelin secretion, while GIP was even stimulatory [16], but in humans no direct evidence was found for either GIP or GLP-1 being involved in the regulation of ghrelin secretion [17], [18]. In contrast, a close inverse association of the plasma levels of GLP-1 and ghrelin after oral glucose ingestion suggested a link between the secretion of both hormones [14], [15]. Since GLP-2 is co-secreted in equimolar amounts along with GLP-1 from intestinal L-cells [19], [20], [21], it is possible that the association between circulating levels of GLP-1 and ghrelin is caused by GLP-2 rather than by GLP-1 itself. This would explain the lack of effect of exogenous GLP-1 administration on ghrelin concentrations in humans [17]. In fact, even though both GLP-1 and GLP-2 arise from the proteolytical cleavage of the same gene product and are secreted under identical conditions, their physiological actions differ in many ways: GLP-1 primarily acts to stimulate insulin secretion [22], [23], inhibit glucagon secretion [22], [24] and decelerate the velocity of gastric emptying [25], [26], while GLP-2 does not affect insulin secretion or gastric emptying, but enhances glucagon release in humans [27]. Moreover, GLP-2 exerts important effects on the intestinal mucosa, where it acutely stimulates nutrient absorption and enhances regeneration [28], [29], [30], [31], whereas GLP-1 might represent an endogenous growth factor for the endocrine pancreas [23], [32]. The effects of GLP-2 on ghrelin secretion have not yet been studied in detail.
Therefore, in the present study, we addressed the following questions: (1) Does exogenous GLP-2 administration affect ghrelin secretion in humans, and (2) which endogenous factors correlate to the circulating ghrelin concentrations in the fasting state?
Section snippets
Study protocol
The study protocol was approved by the ethics committee of the Ruhr-University of Bochum on March 14th, 2002 (registration number: 1839) prior to the study. Written informed consent was obtained from all participants.
Study design and study subjects
Parts of this study have been reported in a previous publication about the effects of GLP-2 on gastric functions, lipid absorption and endocrine pancreatic secretion [27].
Screening visit: At a screening visit, blood was drawn from all participants in the fasting state for
Statistical analysis
Results are reported as mean ± SEM. All statistical calculations were carried out using paired repeated measures analysis of variance (ANOVA) using Statistica Version 5.0 (Statsoft Europe, Hamburg, Germany). This analysis provides p-values for the overall differences between the experiments (A), differences over time (B), and for the interaction of experiment with time (AB). If a significant interaction of treatment and time (AB) was documented (p < 0.05), values at single time points were compared
Time course of ghrelin concentrations during GLP-2 administration
During the infusion of GLP-2, plasma concentrations of intact GLP-2 increased from 10.0 ± 1.5 pmol/l to steady-state levels of 207.7 ± 8.3 pmol/l, and returned to baseline values within 60 min after cessation of the infusion (Fig. 1; p < 0.0001 for the time course). In contrast, GLP-2 plasma levels remained unchanged during placebo administration (p < 0.0001 vs. GLP-2 administration).
Basal plasma levels (− 30 to 0 min) of ghrelin were similar during the experiments with GLP-2 and placebo administration (
Discussion
The present study was undertaken to investigate the effects of exogenous GLP-2 on fasting ghrelin concentrations in humans. We report an ∼ 10% inhibition of ghrelin secretion by GLP-2 that was reversible after cessation of GLP-2 administration. Furthermore, there was a strong linear relationship between the circulating levels of glucose and insulin with fasting ghrelin levels, whereas glucagon appeared to be less important for the control of basal ghrelin secretion.
There has been a debate as to
Acknowledgements
The excellent technical assistance of Birgit Baller and Lone Bagger is greatly acknowledged. This study was supported by grants from the Wilhelm-Sander-Stiftung (grant no. 2002.025.1 to JJM), the Deutsche Forschungsgemeinschaft (Me 2096/3-1) and the Deutsche Diabetes Gesellschaft (DDG to JJM).
References (48)
- et al.
Ghrelin-producing cells exist as two types of cells, closed-and opened-type cells, in the rat gastrointestinal tract
Peptides
(2002) - et al.
Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin
Gastroenterology
(2001) - et al.
Ghrelin acts in the central nervous system to stimulate gastric acid secretion
Biochem Biophys Res Commun
(2001) - et al.
Effect of GIP, GLP-1, insulin and gastrin on ghrelin release in the isolated rat stomach
Regul Pept
(2004) - et al.
Ghrelin is not suppressed in hyperglycemic clamps by gastric inhibitory polypeptide and arginine
Regul Pept
(2005) - et al.
Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans
Gastroenterology
(2006) - et al.
Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon
Gastroenterology
(2001) - et al.
Structure, measurement, and secretion of human glucagon-like peptide-2
Peptides
(2000) - et al.
Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety
Regul Pept
(2003) - et al.
Glucagon-like peptide (GLP)-2 action in the murine central nervous system is enhanced by elimination of GLP-1 receptor signaling
J Biol Chem
(2001)