Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Abstract

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 μg·kg−1·h−1 GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals ( P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression ( P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

Glucagon-Like Peptide 2 Increases Efficacy of Distraction Enterogenesis

“…This is evident through the increased expression of SGLT1 in the GLP-2 stretch group compared to the PEG stretch group. This matches previous studies where GLP-2 was shown to increase SGLT1 expression in short bowel resection model (38) and in tissue-engineered neointestine (39). Therefore, GLP-2 appears to contribute to increases of SGLT1 expression in these models of intestinal growth, regardless of the approach.…”

Exogenous Glucagon‐Like Peptide‐2 (GLP‐2) Augments GLP‐2 Receptor mRNA and Maintains Proglucagon mRNA Levels in Resected Rats

“…9 This study uses a low dose of GLP-2 (100 μg/kg body weight/d) compared with similar studies in which GLP-2 was also given to animals undergoing bowel resection, with doses ranging from approximately 200 to 240 μg/kg body weight/d. 16,17 This dose was chosen based on a dose response study conducted in parenteral nutrition-fed rats as the lowest dose that would restore plasma GLP-2 concentrations to those of orally fed rats. 22 The dose was previously shown to induce adaptation in a parenteral nutrition-dependent rat model of SBS.…”

“…GLP-2 administration augments the adaptive response to massive intestinal resection in animal models receiving oral feedings alone and in SBS models using parenteral nutrition, or parenteral nutrition plus supplemental enteral nutrients. [14][15][16][17] In human studies, GLP-2 improves absorption and nutrition parameters in patients with reduced endogenous GLP-2 secretion due to massive bowel resection and SBS. 18 Clinical trials using teduglutide, a GLP-2 analogue resistant to degradation by dipeptidyl peptidase IV, have shown safety and evidence of adaptation in patients with SBS.…”

New growth factor therapies aimed at improving intestinal adaptation in short bowel syndrome

“…Martin et al and Scott et al have demonstrated that GLP-2 administration following resection causes significant increases in a variety of morphological parameters including total and mucosal wet weights, crypt villus height, intestinal protein and DNA content, and crypt cell proliferation when compared with untreated resected animals. 108,109 Conversely, GLP-2 immunoneutralization of SBS mice causes inhibition of intestinal epithelia hyperplasia. 112 In addition GLP-2 administration enhanced the absorptive capacity of the residual bowel, increasing sucrase activity and expression of the sodium-dependent glucose cotransporter-1 cotransporter, compared with untreated resected animals that did not receive GLP-2 supplementation.…”