Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators.
Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone that affects multiple facets of intestinal physiology, including growth, barrier function, digestion, absorption, motility, and blood flow. The mechanisms through which GLP-2 produces these actions are complex, involving unique signaling mechanisms and multiple indirect mediators. As clinical trials have begun for the use of GLP-2 in a variety of intestinal disorders, the elucidation of such mechanisms is vital. The GLP-2 receptor (GLP-2R) is a G protein-coupled receptor, signaling through multiple G proteins to affect the cAMP and mitogen-activated protein kinase pathways, leading to both proliferative and antiapoptotic cellular responses. The GLP-2R also demonstrates unique mechanisms for receptor trafficking. Expression of the GLP-2R in discrete sets of intestinal cells, including endocrine cells, subepithelial myofibroblasts, and enteric neurons, has led to the hypothesis that GLP-2 acts indirectly through multiple mediators to produce its biological effects. Indeed, several studies have now provided important mechanistic data illustrating several of the indirect pathways of GLP-2 action. Thus, insulin-like growth factor I has been demonstrated to be required for GLP-2-induced crypt cell proliferation, likely involving activation of beta-catenin signaling. Furthermore, vasoactive intestinal polypeptide modulates the actions of GLP-2 in models of intestinal inflammation, while keratinocyte growth factor is required for GLP-2-induced colonic mucosal growth and mucin expression. Finally, enteric neural GLP-2R signaling affects intestinal blood flow through a nitric oxide-dependent mechanism. Determining how GLP-2 produces its full range of biological effects, which mediators are involved, and how these mediators interact is a continuing area of active research.
Dubé
Philip E
PE
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Brubaker
Patricia L
PL
D000818:Animals; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism* / Q000502:physiology*; D000067758:Glucagon-Like Peptide-2 Receptor; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D008954:Models, Biological; D018027:Receptors, Glucagon / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D018027:Receptors, Glucagon