Tales beyond the crypt: glucagon-like peptide-2 and cytoprotection in the intestinal mucosa.

Intestinal function and mucosal epithelial integrity are regulated by the combined actions of different hormonal and neuronal signals. Enteral nutrition is an essential determinant of mucosal epithelial function, and peptide hormones released after nutrient ingestion regulate gastric motility, pancreatic and biliary secretions, nutrient transport, and the growth and differentiated actions of the mucosal epithelium. Examples of these gut-derived hormones include gastrin, glucose-dependent insulinotropic polypeptide, cholecystokinin, neurotensin, peptide YY, secretin, and the proglucagon-derived peptides glicentin, oxyntomodulin, glucagonlike peptide (GLP)-1, and GLP-2. Several of these peptides exhibit growth-promoting properties on the intestinal epithelial mucosa in vivo, such as glicentin, peptide YY, cholecystokinin, progastrin, and glycine-extended gastrin. The identification of GLP-2 as a potent intestinotrophic hormone in rodents (1) sparked substantial interest in understanding how the biological actions of this peptide are transduced into growth signals for the gut mucosa. GLP-2 is a 33-amino-acid peptide hormone derived by posttranslational processing of proglucagon in enteroendocrine cells of both the small and large bowel and in specific regions of the brainstem. Circulating levels of GLP-2 rise rapidly after ingestion of nutrients, and the intact peptide is rapidly degraded to an inactive metabolite, GLP-2(3–33), via the enzyme dipeptidyl peptidase IV (2, 3). In addition to its potent trophic effects on the intestinal mucosa, GLP-2 inhibits gastric emptying and gastric acid secretion, stimulates intestinal barrier function (4), stimulates intestinal hexose transport (5), and enhances nutrient absorption in rodents and in human patients with short bowel syndrome (6). GLP-2 appears to mimic at least some of the effects of enteral nutrition on the mucosal epithelium, as GLP-2 administration prevents the mucosal hypoplasia that develops in parenterally fed animals, in part by reducing proteolysis and crypt cell apoptosis (7, 8). Although a specific receptor for GLP-2 has been identified that is expressed in the small and large bowel (9–11), the mechanisms activated by GLP-2 that produce growth and inhibit apoptosis in the gut remain poorly understood. The study by Burrin et al. (12) in this issue of Endocrinology addresses the cellular mechanisms by which GLP-2 induces cell survival and prevents intestinal atrophy in piglets maintained on parenteral nutrition. Burrin et al. demonstrate that constant administration of GLP-2 for 7 d at three different infusion rates reveals dose-dependent effects of GLP-2 on proliferation and cytoprotection in the absence of enteral nutrients. Although GLP-2 significantly inhibited cell death in the gut epithelium at lower infusion doses (2.5–5.0 nmol/ kg), enhanced crypt cell proliferation and up-regulation of endothelial nitric oxide synthase expression was only observed at the highest GLP-2 infusion rate (10 nmol/kg). Furthermore, the authors provide evidence suggesting that the cytoprotective actions of GLP-2 in the intestinal mucosa were associated with reduced activation of caspase 3 and 6, increased Bcl-2 expression, phosphorylation of protein kinase B/Akt, and inactivation of the proapoptotic molecule glycogen synthase kinase-3. The authors suggest that physiological levels of GLP-2 achieved in the postprandial state, which approximate but are likely to be less than the circulating levels of GLP-2 obtained in the experimental group receiving the lowest infusion rate of the peptide, may act to maintain intestinal integrity and prevent cellular damage. In contrast, much higher circulating levels of GLP-2 are required to prevent parenteral nutrition-induced intestinal atrophy and stimulate mucosal proliferation. Thus, the antiapoptotic mechanisms engaged by the GLP-2 receptor (GLP2R) appear more sensitive to lower plasma levels of GLP-2, whereas activation of the GLP-2R, leading to enhanced cell proliferation, apparently requires much higher levels of GLP-2. This study provides new insights into the cellular mechanisms by which GLP-2 may protect the intestinal mucosa from damage in vivo. The GLP-2R, a G protein-coupled receptor (9) structurally related to but distinct from the glucagon and GLP-1 receptors, has been shown to exhibit a highly restricted pattern of expression in human enteroendocrine cells (10), murine enteric neurons (11), and in multiple regions of the rodent brain (13). Due to the relatively exclusive localization of the GLP-2R, efforts directed at identifying the mechanism(s) by which GLP-2 exerts its myriad effects in the gut epithelium are focused on the identification of indirect mediators of GLP-2 action liberated by the enteric nervous system or gut endocrine cells (Fig. 1). The intestinotrophic effects of GLP-2 that result in expansion of the normal mucosal epithelium are largely due to stimulation of crypt cell proliferation and, to a lesser extent, inhibition of crypt cell apoptosis. These proliferative and cytoprotective effects of GLP-2 lead to lengthening of the intestinal villi and expansion of mucosal absorptive surface area, accompanied by a modest expansion of the crypt compartment. Because the GLP-2R does not appear to be directly expressed in normal crypt cells or enterocytes, proliferation and expansion of the mucosal epithelium is thought to occur by indirect mechanisms activated by GLP-2R signaling, possibly via stimulated release of presently unidentified growth and cytoprotective factors (Fig. 1). Although inhibition of cell death does not appear to contribute greatly to GLP-2induced mucosal expansion in the healthy bowel, exogenous Abbreviations: GLP, Glucagon-like peptide; GLP-2R, GLP-2 receptor.