HOT TOPIC Glucagon-Like Peptide 2*

Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide-encoded carboxyterminal to the sequence of GLP-1 in the proglucagon gene. Both GLP-1 and GLP-2 are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms of action. GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP-2 significantly enhances the surface area of the mucosal epithelium via stimulation of crypt cell proliferation and inhibition of apoptosis in the enterocyte and crypt compartments. The cytoprotective and reparative effects of GLP-2 are evident in rodent models of experimental intestinal injury. GLP-2 reduces mortality and decreases mucosal injury, cytokine expression, and bacterial septicemia in the setting of small and large bowel inflammation. GLP-2 also enhances nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. The actions of GLP-2 are transduced by the GLP-2 receptor, a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon. Activation of GLP-2 receptor signaling in heterologous cells promotes resistance to apoptotic injury in vitro. The cytoprotective, reparative, and energy-retentive properties of GLP-2 suggests that GLP-2 may potentially be useful for the treatment of human disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium. (J Clin Endocrinol Metab 86: 1759–1764, 2001) T GLUCAGON-LIKE PEPTIDES (GLPs) are produced in open type gut endocrine cells of the small and large intestine and play diverse roles in the regulation of energy homeostasis. Food ingestion sets in motion coordinated peptidergic responses that regulate nutrient transit through the gut, and nutrient absorption. Gut peptides also contribute to optimization of mucosal epithelial function for nutrient digestion and absorption. Following nutrient absorption into the blood stream, enteroendocrine-derived peptides such as GLP-1 facilitate nutrient disposal by regulating islet hormones and, indirectly, energy absorption via effects on liver, muscle, and adipose tissue. The aim of this review is to highlight recent advances in our understanding of the role played by GLP-2 in the regulation of intestinal epithelial biology and nutrient absorption. The sequence of proglucagon contains a number of distinct peptides with pleiotropic actions, including glicentin, glucagon, oxyntomodulin, and two GLPs as well as two intervening or spacer peptides (Fig. 1). Whereas glucagon, GLP-1, and GLP-2 exert well-defined actions through known receptors, the biological actions of the remaining proglucagonderived peptides remain less well characterized. Furthermore, no receptors have yet been isolated for glicentin, oxyntomodulin, or the intervening peptides (1–4). Although the sequence of GLP-2 was not detected in anglerfish islet proglucagon complementary DNAs (cDNAs; Ref. 5), the GLP-2 sequence (Fig. 2) was detected in all isolated mammalian proglucagon cDNAs and genes (6–10) as a 33 amino acid peptide located carboxyterminal to GLP-1 and intervening peptide 2 (Figs. 1 and 2). Subsequent studies demonstrated that fish, chickens, and lizards generate GLP-2 in the gut as a result of tissue-specific alternative RNA splicing of proglucagon RNA transcripts (11, 12). In mammals, tissue-specific posttranslational processing liberates GLP-2 from proglucagon in the intestine and brain but not in pancreas, as a result of cell-specific expression of prohormone convertases in gut endocrine cells (13). Isolation and sequencing of GLP-2 from the porcine and human intestine confirmed that GLP-2 is a 33 amino acid peptide (Fig 2), corresponding to proglucagon 126–158, ending in a carboxyterminal Asp residue (14, 15). Initial studies of GLP-2 biological activity demonstrated increased adenylate cyclase activity in rat hypothalamic and pituitary membrane preparations following incubation with 50 pm GLP-2 (16). Subsequent analyses of GLP-2 activity in the gut either failed to demonstrate activity of GLP-2 or demonstrated GLP-2-mediated inhibition of serum-stimulated intestinal cell growth in vitro (17). Nevertheless, despite these negative findings, considerable experimental evidence correlated increased expression and secretion of intestinal proglucagon-derived peptides (PGDPs) with bowel injury and mucosal growth of the small intestine (18–22). Furthermore, two patients with glucagonomas exhibited marked small bowel villus hyperplasia that was reversed following surgical removal of the tumor (23, 24). Following observaReceived October 4, 2000. Revision received December 8, 2000. Accepted December 27, 2000. Address correspondence and requests for reprints to: Dr. D. J. Drucker, Toronto General Hospital, 101 College Street CCRW3-845, Toronto, Ontario, Canada M5G 2C4. E-mail: [email protected]. * Studies from the Drucker laboratory are supported by an operating grant from the Canadian Institute of Health Research and the Ontario Research and Development Challenge Fund. † Senior Scientist of the Canadian Institute of Health Research, a consultant to NPS Allelix Corp., and a party to a glucagon-like peptide 2-related licensing agreement between the University of Toronto, the Toronto General Hospital, and NPS Allelix Corp. 0021-972X/01/$03.00/0 Vol. 86, No. 4 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society