Abstract
Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p<0.0001) and an increased concentration of GLP-2 in the pancreas of Gcgr-/- mice, coinciding with an increase in small intestinal (p<0.0001) and colonic (p<0.05) weight. Increased villus height was recorded in the duodenum (p<0.001) and crypt depth was increased in the duodenum and jejunum (p<0.05 and p<0.05). Disruption of glucagon receptor signaling did not affect body weight during AOM/DSS treatment, neither did it affect the inflammatory score assessed during colonoscopy or the number of large and small adenomas present at the end of the study period. In conclusion, despite the increased endogenous GLP-2 secretion Gcgr-/- mice were not more susceptible to AOM/DSS-induced tumors.
Highlights
The glucagon-like peptides (GLPs) are post-translational cleavage products of the precursor polypeptide proglucagon [1, 2]
Extractable GLP-2 in the pancreas could not be detected in Gcgr+/+ mice but was present in the Gcgr−/− mice at a concentration of 38 ± 15 pmol/g protein (p
Benefits to patients include an increase in intestinal wet weight and absorption [27] leading to a reduction in parenteral nutrition volume requirements, but exogenous GLP-2 administration in animal models has been linked to the acceleration of neoplastic growth [13, 14]
Summary
The glucagon-like peptides (GLPs) are post-translational cleavage products of the precursor polypeptide proglucagon [1, 2]. Administration of exogenous GLP-2 increases intestinal proliferation, decreases apoptosis [6], improves nutrient absorption [7], enhances barrier function [8] and intestinal blood flow [9, 10], and it can be demonstrated that endogenous GLP-2 mediates adaptive regrowth after a period of nutrient deprivation [11] These intestinotrophic features of GLP-2 have guided the hormone’s therapeutic potential for the treatment of intestinal injury, culminating in the FDA approval of the DPP-4 resistant human GLP-2 analog teduglutide for the treatment of adults and children aged 1 and over for short bowel syndrome, who are receiving parenteral support [12]. The lack of consensus in the literature regarding the tumor-promoting effect of GLP-2 warrants further investigations; in addition, the effects of chronically elevated levels of endogenous GLP-2 and its potential contribution to neoplastic development have never been investigated
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