ABSTRACT
BACKGROUND: After massive small bowel resection, the remnant intestine undergoes compensatory adaptation. We tested the hypothesis that glucagon-like peptide-2 (GLP-2) is an endogenous mediator of postresection intestinal adaptation. METHODS: Rats were allocated to 1 of 4 groups: groups 1 and 2 rats underwent mid-small bowel transection and reanastomosis; groups 3 and 4 rats underwent 75% mid-small bowel resection and reanastomosis. Groups 2 and 4 rats were administered 1.8 mg of antirat GLP-2 antibody twice daily beginning immediately after the surgical procedure; groups 1 and 3 rats were administered rabbit serum (control). Ileal specimens were harvested on postoperative day 7. RESULTS: Ileal mucosa from group 3 animals displayed morphologic and proliferative indices of adaptation. Each of these indices of adaptation was inhibited by GLP-2 immunoneutralization (group 4). Morphologic and proliferative parameters in the ileum from animals that had undergone transection with reanastomosis were unaffected by GLP-2 immunoneutralization. CONCLUSIONS: These results suggest that GLP-2 is an endogenous mediator of postresection intestinal adaptation.
Subject(s)
Adaptation, Physiological , Antibodies/administration & dosage , Ileum/surgery , Intestinal Mucosa/growth & development , Peptides/physiology , Anastomosis, Surgical , Animals , Disease Models, Animal , Glucagon-Like Peptide 2 , Glucagon-Like Peptides , Ileum/growth & development , Intestinal Mucosa/metabolism , Intestine, Small/growth & development , Intestine, Small/surgery , Male , Peptides/immunology , Random Allocation , Rats , Rats, Sprague-DawleyABSTRACT
Glucagon-like peptide 2 (GLP-2) is a 33-amino acid gut peptide that leads to villus hyperplasia and altered gene expression. We examined the effect of chronically administered GLP-2 on diurnal gene expression rhythms using the Na+/glucose cotransporter 1 (SGLT1) as the index. Animals were treated with [Gly2]GLP-2 (twice daily; 1microg/g body weight) or vehicle (control) for 10 days. Rats were killed at either 3 hr or 9 hr after light onset (ZT3 and ZT9, respectively), an interval during which SGLT1 expression exhibits a robust induction. SGLT1 mRNA expression was assessed by Northern blotting and in situ hybridization. SGLT1 protein was examined by immunofluorescence and Western blotting. Tissues from GLP-2-treated rats had increased villus height, crypt depth, and proliferation index (P < 0.05). GLP-2 administration did not alter the diurnal increase in mRNA levels of SGLT1, GLUT2, or GLUT5. However, in GLP-2-treated rats, the SGLT1 protein amount increased at both ZT3 and ZT9. Moreover, SGLT1 was preferentially localized to the apical membranes in this group. GLP-2 does not adversely affect the diurnal expression rhythm of SGLT1 and appears to increase membrane expression of the protein. These biological actions of GLP-2 may contribute to its therapeutic value in intestinal diseases.
Subject(s)
Circadian Rhythm/physiology , Gastrointestinal Hormones/pharmacology , Gene Expression Regulation/drug effects , Membrane Glycoproteins/biosynthesis , Monosaccharide Transport Proteins/biosynthesis , Peptides/pharmacology , Animals , Circadian Rhythm/drug effects , Glucagon-Like Peptide 2 , Glucagon-Like Peptides , Glucose Transporter Type 2 , Glucose Transporter Type 5 , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Light , Male , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Sodium-Glucose Transporter 1 , Time FactorsABSTRACT
BACKGROUND: Glucagon-like peptide 2 (GLP-2) is a potent intestinotrophic peptide that enhances recovery following intestinal injury. We tested the hypothesis that GLP-2 acutely enhances intestinal epithelial restitution. MATERIAL AND METHODS: Rat jejunal segments were mounted in Ussing chambers. HCl (10 mM) was applied to the mucosal surfaces for 10 min to induce injury. Tissues were then lavaged with modified Ringer's solution and maintained in the chambers for an additional 3 h. Tissues were treated with 10 microM GLP-2 or vehicle alone (control). Electrical parameters were recorded, and tissues were salvaged for morphometric analysis. RESULTS: GLP-2-treated tissues exhibited a significantly greater recovery of potential difference and resistance (P < 0.05) than did controls. Morphometric analysis revealed that columnar cells covered a greater percentage of the epithelial surface in GLP-2-treated tissues than in controls (P < 0.05). CONCLUSIONS: These results suggest that GLP-2 acutely enhances intestinal epithelial restitution following acid-induced injury. This novel biological action of GLP-2 may contribute to its therapeutic effect in models of intestinal disease.
