M1823 Synergistic Intestinal Growth in Parenterally-Fed Rats Given Supplemental Enteral Nutrients (SEN) and a Low-Dose of GLP-2 Is Correlated with Greater Proglucagon and IGF-I Expression in Ileum

Abstract

Background: Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that stimulates intestinal adaptation through unknown pathways, possibly IGFI. Objective: To determine the mechanisms underlying the synergistic growth response to combination treatment with SEN and a low-dose of GLP-2 in parenterally-fed rats. Methods: Rats were randomized to 4 treatment groups and maintained with TPN for 7 days: total parenteral nutrition (TPN) alone, parenteral nutrition (PN)+SEN, TPN+GLP-2, PN+SEN+GLP-2 (combination treatment), n=9/group. The 2 main treatment effects are: ±GLP-2 (100 μg/kg body wt/day) and ± SEN (40% of energy needs, day4-6). Results: Single treatment with GLP-2 and combination treatment with SEN+GLP-2 induced significant enterocytes proliferation in ileum based on the number of BrdU labeled crypt cells (TPN alone=6±1, PN+SEN=5±0, TPN+GLP-2=10±1*, and PN+SEN+GLP-2=8±1*). Plasma concentrations of bioactive GLP-2 were significantly increased in TPN+GLP-2 compared to TPN alone and further increased by 22% in combination treatment suggesting a synergistic effect (SEN×GLP-2 interaction, p=0.0987). Combination treatment significantly decreased plasma dipeptidyl peptidase IV (DPPIV) activity compared to either treatment alone. There was no significant difference in plasma IGF-I level among groups. A synergistic effect of combination treatment to significantly increase proglucagon mRNA expression was noted in ileum whereas single treatment with either GLP-2 or SEN did not significantly alter proglucagon expression compared to TPN alone (TPN alone=0.04±0.02, PN+SEN=0.19±0.07, TPN+GLP-2= 0.17±0.09, and PN+SEN+GLP-2=0.33±0.14*; SEN×GLP-2 interaction, p=0.0072). Plasma concentrations of bioactive GLP-2 were positively correlated with ileal proglucagon mRNA expression in both +GLP-2 and -GLP-2 groups (p 0.44). PN+SEN did not alter IGF-I mRNA expression in jejunum and ileum compared to TPN alone whereas TPN+GLP-2 significantly increased IGF-I mRNA expression in ileum. Combination treatment significantly increased IGF-I mRNA expression in both jejunum and ileum. Jejunal and ileal IGF-I mRNA expressions were positively correlated with ileal proglucagon mRNA expression (p 0.42). Conclusions: Combination treatment with SEN+GLP-2 induced synergistic growth resulting in greater concentrations of bioactive GLP-2 in plasma and greater mucosal cellularity in ileum in parenterally-fed rats. These findings suggest that GLP2 provides a stimulus for proliferation of enterocytes that is associated with greater express of ileal proglucagon and IGF-I mRNA and a decrease in plasma DPPIV activity.