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.

Figure 1

Ghrelin affects multiple systems. Ghrelin is secreted mainly by the stomach, but has effects in multiple areas, including the CNS, the immune system, the adrenal gland and the cardiovascular system. Ghrelin can also affect the proliferation of osteoblasts and neoplastic cells. Abbreviations: CNS, central nervous system; GH, growth hormone.

Figure 2

Effects of ghrelin on digestive functions of the upper gastrointestinal tract. Ghrelin can affect digestive functions by vagal signaling, directly within the enteric nervous system or within the CNS after crossing the blood–brain barrier. Ghrelin stimulates gastric and small-intestinal motor functions and inhibits insulin release from the pancreas. Abbreviations: CNS, central nervous system; MMC, migrating motor complexes.

Figure 3

Effect of ghrelin and ghrelin antagonists on insulin secretion. a | Ghrelin decreased and a ghrelin antagonist ([D-Lys³]-GHRP-6) increased plasma levels of insulin. b | In gastrectomized rats, the ghrelin antagonist still increased insulin, which suggests a direct effect on pancreatic secretion of insulin. Copyright © 2006 American Diabetes Association From Diabetes^®, Vol. 55, 2006; 3486–3493. Reprinted with permission from The American Diabetes Association.