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Actions and therapeutic pathways of ghrelin for gastrointestinal disorders

Abstract

Ghrelin is a peptide hormone that possesses unique orexigenic properties. By acting on the growth-hormone secretagogue receptor 1a, ghrelin induces a short-term increase in food consumption, which ultimately induces a positive energy balance and increases fat deposition. Reduced ghrelin levels have been observed in obese patients and after bariatric surgery. In particular, bariatric procedures that involve gastric resection or bypass lead to reduced ghrelin levels. Administration of physiological doses of exogenous ghrelin to humans does not significantly alter gastric motility; however, administration of high doses stimulates gastric motility, with increased gastric tone and emptying, and increased activity of migrating motor complexes in the small bowel. The potential of ghrelin agonists to be used as prokinetics is being tested in patients with gastroparesis and postoperative ileus. Ghrelin acts directly on pancreatic islet cells to reduce insulin production. Findings from studies in animals have revealed that small-molecule ghrelin antagonists favorably influence glucose tolerance, appetite suppression and weight loss. Other studies have demonstrated that ghrelin antagonists retard gastric emptying only at very high doses, which suggests that these agents will probably not induce upper gastrointestinal symptoms. The potential of this new class of therapeutic agents to influence appetite and glycemic control strongly indicates that they should be tested in clinical trials.

Key Points

  • Serum levels of ghrelin are reduced in obese individuals

  • Whether the reduced ghrelin levels observed in patients after bypass bariatric surgery are a cause of weight loss or a consequence of the procedure is unclear

  • Ghrelin agonists accelerate gastric emptying and could potentially be used to treat gastroparesis and postoperative ileus

  • Ghrelin antagonists are unlikely to delay gastric emptying or to cause upper gastrointestinal symptoms

  • Small-molecule ghrelin-receptor antagonists improve glucose tolerance, suppress appetite and promote weight loss in animals; their safety and efficacy in humans should be tested in clinical trials

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Figure 1: Ghrelin affects multiple systems.
Figure 2: Effects of ghrelin on digestive functions of the upper gastrointestinal tract.
Figure 3: Effect of ghrelin and ghrelin antagonists on insulin secretion.

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Acknowledgements

M. Camilleri is funded in part by grants RO1-DK54681, RO1-DK67071 and K24-DK02638 from the NIH. A. Papathanasopoulos is funded by an international grant of the Hellenic Society of Gastroenterology.

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Camilleri, M., Papathanasopoulos, A. & Odunsi, S. Actions and therapeutic pathways of ghrelin for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol 6, 343–352 (2009). https://doi.org/10.1038/nrgastro.2009.72

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