Elsevier

Regulatory Peptides

Volume 137, Issue 3, 10 December 2006, Pages 173-178
Regulatory Peptides

Glucagon-like peptide 2 inhibits ghrelin secretion in humans

https://doi.org/10.1016/j.regpep.2006.07.009Get rights and content

Abstract

Introduction

The growth hormone secretagogue receptor ligand ghrelin is known to play a pivotal role in the central nervous control of energy homeostasis. Circulating ghrelin levels are high under fasting conditions and decline after meal ingestion, but the mechanisms underlying the postprandial drop in ghrelin levels are poorly understood. In the present study we addressed, whether (1) exogenous GLP-2 administration decreases ghrelin levels and (2) what other endogenous factors are related to ghrelin secretion under fasting conditions.

Patients and methods

Fifteen healthy male volunteers were studied with the intravenous infusion of GLP-2 (2 pmol l 1 min 1) or placebo over 120 min in the fasting state. Plasma concentrations of glucose, insulin, C-peptide, glucagon, intact GLP-2 and ghrelin were determined.

Results

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 (p < 0.0001). Administration of GLP-2 led to an ∼ 10% reduction in ghrelin concentrations, whereas placebo administration was without an effect (p < 0.001). After cessation of the GLP-2 infusion, ghrelin levels returned to baseline values, and were no longer different from those in the placebo experiments. There was a strong inverse linear relationship between the fasting concentrations of ghrelin and the respective levels of glucose, insulin and C-peptide (r = 0.49, p < 0.01; r = 0.55, p < 0.01 and r = 0.59, p < 0.001, respectively). In contrast, there was no detectable association between fasting ghrelin levels and the ambient concentrations of glucagon or intact GLP-2.

Conclusions

GLP-2 inhibits ghrelin secretion in humans at plasma levels of ∼ 200 pmol/l. However, the physiological importance of this effect appears to be minor compared to the actions of insulin and glucose.

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)

  • B. Yusta et al.

    Enteroendocrine localization of GLP-2 receptor expression in humans and rodents

    Gastroenterology

    (2000)
  • C. Dornonville de la Cour et al.

    A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control

    Regul Pept

    (2001)
  • M. Kojima et al.

    Ghrelin is a growth-hormone-releasing acylated peptide from stomach

    Nature

    (1999)
  • Y. Date et al.

    Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

    Endocrinology

    (2000)
  • M. Tschop et al.

    Ghrelin induces adiposity in rodents

    Nature

    (2000)
  • M. Nakazato et al.

    A role for ghrelin in the central regulation of feeding

    Nature

    (2001)
  • A.M. Wren et al.

    The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion

    Endocrinology

    (2000)
  • E. Arvat et al.

    Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans

    J Endocrinol Investig

    (2000)
  • A.M. Wren et al.

    Ghrelin enhances appetite and increases food intake in humans

    J Clin Endocrinol Metab

    (2001)
  • F. Broglio et al.

    Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans

    J Clin Endocrinol Metab

    (2001)
  • D.E. Cummings et al.

    A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

    Diabetes

    (2001)
  • D.E. Cummings et al.

    Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery

    N Engl J Med

    (2002)
  • C.B. Djurhuus et al.

    Circulating levels of ghrelin and GLP-1 are inversely related during glucose ingestion

    Horm Metab Res

    (2002)
  • C.B. Djurhuus et al.

    Feast or famine — are GLP-1 and ghrelin secretion intertwined?

    Horm Metab Res

    (2002)
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