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

Abstract

Background: Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon-derived hormone that stimulates intestinal adaptive growth. Our aim was to determine whether exogenous GLP-2 increases resection-induced adaptation without diminishing endogenous proglucagon and GLP-2 receptor expression. Methods: Rats underwent transection or 70% jejunoileal resection ± GLP-2 infusion (100 μg/kg body weight/d) and were fed a semipurified diet with continuous infusion of GLP-2 or saline by means of jugular catheter. After 7 days, body weight, mucosal cellularity (dry mass, protein and DNA), crypt–villus height, and crypt cell proliferation (by bromodeoxyuridine staining) were determined. Plasma bioactive GLP-2 (by radioimmunoassay), proglucagon and GLP-2 receptor mRNA expression (by Northern blot and real-time reverse transcriptase quantitative polymerase chain reaction) were measured. GLP-2 receptor was colocalized to neuroendocrine markers by immunohistochemistry. Results: Low-dose exogenous GLP-2 increased mucosal cellularity and crypt–villus height in the duodenum, jejunum, and ileum; enterocyte proliferation in the jejunal crypt; and duodenal and jejunal sucrase segmental activity. Plasma bioactive GLP-2 concentration increased 70% upon resection, with an additional 54% increase upon GLP-2 infusion in resected rats (P < .05). Ileal proglucagon mRNA expression increased with resection, and exogenous ileum GLP-2 failed to blunt this response. Exogenous GLP-2 increased ileum GLP-2 receptor expression 3-fold in resected animals and was colocalized to vasoactive intestinal peptide-positive and endothelial nitric oxide synthase-expressing enteric neurons and serotonin-containing enteroendocrine cells in the jejunum and ileum of resected rats. Conclusions: Exogenous GLP-2 augments adaptive growth and digestive capacity of the residual small intestine in a rat model of mid–small bowel resection by increasing plasma GLP-2 concentrations and GLP-2 receptor expression without diminishing endogenous proglucagon expression.

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