Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators

• Published in: American journal of physiology: endocrinology and metabolism 2007-08, Vol.293 (2), p.E460-E465
• Main Authors: Dube, Philip E, Brubaker, Patricia L
• Format: Article
• Language: English
• Subjects: Animals; Cellular biology; Gene expression; Glucagon-Like Peptide 2 - metabolism; Glucagon-Like Peptide 2 - physiology; Glucagon-Like Peptide-2 Receptor; Growth hormones; Humans; Intestinal Mucosa - cytology; Intestinal Mucosa - growth & development; Intestinal Mucosa - physiology; Kinases; Models, Biological; Peptides; Receptors, Glucagon - physiology; Signal Transduction - physiology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00149.2007

Departments of 1 Physiology and 2 Medicine, University of Toronto, Toronto, Ontario, Canada Submitted 7 March 2007 ; accepted in final form 13 April 2007 ABSTRACT 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 -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. growth; intestine; receptor; signaling Address for reprint requests and other correspondence: P. L. Brubaker, Rm. 3366, 1 King's College Cir., Toronto, ON M5S 1A8, Canada (e-mail: p.brubaker{at}utoronto.ca )