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      Ghrelin Is Suppressed by Glucagon and Does Not Mediate Glucagon-Related Growth Hormone Release

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          Background:Glucagon stimulation is routinely used as a provocative test to assess growth hormone (GH) sufficiency in pediatrics. Ghrelin also markedly stimulates GH secretion. Because glucagon stimulates the promoter of the ghrelin gene in vitro as well as ghrelin secretion by the perfused rat stomach, we sought todetermine whether ghrelin mediates glucagon-induced GH secretion. Methods: We compared ghrelin, GH, insulin and glucose responses following administration of 0.03 mg/kg intravenously (iv; max. 1 mg) and 0.1 mg/kg intramuscularly (im; max. 2 mg) of glucagon in two groups (n = 10–11/group) of GH-sufficient children. We also measured ghrelin before and 6 min after iv administration of 1 mg glucagon in 21 adult subjects. Results: In children, glucagon caused a 26% decrease in ghrelin and a 72% increase in glucose concentrations that were independent of the dose or administration route of glucagon. In contrast, the insulin response was 2–3 times higher following administration of 0.1 mg/kg im compared to 0.03 mg/kg of glucagon iv. There was a significant correlation between the maximum decrease in ghrelin and increases in glucose (p = 0.03) but not in insulin. There was a significant correlation between ghrelin and GH area under the curve after controlling for the dose of glucagon (p = 0.03) but not for the maximum increase in glucose.In normal adults, glucagon administration caused a 7% decrease in ghrelin concentrations after 6 min (p = 0.0002). Conclusion: Ghrelin does not play a causal role in the GH response to pharmacological glucagon administration, which suppresses ghrelin levels starting a few minutes after injection.

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          Most cited references 31

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          A receptor in pituitary and hypothalamus that functions in growth hormone release.

          Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
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            Deletion of ghrelin impairs neither growth nor appetite.

            Pharmacological studies show that ghrelin stimulates growth hormone release, appetite, and fat deposition, but ghrelin's physiological role in energy homeostasis has not been established. Ghrelin was also proposed to regulate leptin and insulin release and to be important for the normal function of stomach, heart, kidney, lung, testis, and placenta. To help determine a definable physiological role for ghrelin, we generated ghrelin-null mice. In contrast to predictions made from the pharmacology of ghrelin, ghrelin-null mice are not anorexic dwarfs; their size, growth rate, food intake, body composition, reproduction, gross behavior, and tissue pathology are indistinguishable from wild-type littermates. Fasting produces identical decreases in serum leptin and insulin in null and wild-type mice. Ghrelin-null mice display normal responses to starvation and diet-induced obesity. As in wild-type mice, the administration of exogenous ghrelin stimulates appetite in null mice. Our data show that ghrelin is not critically required for viability, fertility, growth, appetite, bone density, and fat deposition and not likely to be a direct regulator of leptin and insulin. Therefore, antagonists of ghrelin are unlikely to have broad utility as antiobesity agents.
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              Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration.

              Ghrelin is a novel gut-brain peptide that binds to the growth hormone secretagogue receptor (GHS-R), thereby functioning in the regulation of growth hormone (GH) release and food intake. Ghrelin-producing cells are most abundant in the oxyntic glands of the stomach. The regulatory mechanism that governs the biosynthesis and secretion of ghrelin has not been clarified. We report that ghrelin mRNA expression in the gastric fundus was increased, but that ghrelin peptide content decreased after a 48-h fast. Both values returned to control levels after refeeding. The ghrelin plasma concentration in the gastric vein and systemic venous blood increased after 24- and 48-h fasts. Furthermore, des-octanoylated ghrelin and n-octanoylated ghrelin were found in rat stomach, with the ratio of des-octanoylated ghrelin to n-octanoylated ghrelin markedly increased after fasting. The ghrelin mRNA level in the stomach also increased after administration of insulin and leptin. Conversely, db/db mice, which are deficient in the leptin receptor, had lower ghrelin mRNA levels than control mice. These findings suggest that this novel gastrointestinal hormone plays a role in the regulation of energy balance. Copyright 2001 Academic Press.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2005
                27 April 2005
                : 63
                : 3
                : 111-118
                aEndocrinology and Diabetes Unit, British Columbia’s Children’s Hospital, University of British Columbia, Vancouver, Canada; bUnité d’Endocrinologie Pédiatrique, Hôpital des Enfants Reine Fabiola, Free University of Brussels, Brussels, Belgium, and cDivision of Metabolism, Endocrinology and Nutrition, University of Washington, VA Puget Sound Health Care System, Seattle, Wash., USA
                84569 Horm Res 2005;63:111–118
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 51, Pages: 8
                Original Paper


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