Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis.
Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in the gastrointestinal tract. GLP-1 actions regulate blood glucose, whereas GLP-2 exerts trophic effects on intestinal mucosal epithelium. Although GLP-1 actions are preserved in diseases such as diabetes, GLP-2 action has not been extensively studied in the setting of intestinal disease. We have now evaluated the biological effects of a human GLP-2 analog in the setting of experimental murine nonsteroidal antiinflammatory drug-induced enteritis. Human (h)[Gly(2)]GLP-2 significantly improved survival whether administered before, concomitant with, or after indomethacin. h[Gly(2)]GLP-2-treated mice exhibited reduced histological evidence of disease activity, fewer intestinal ulcerations, and decreased myeloperoxidase activity in the small bowel (P < 0.05, h[Gly(2)]GLP-2- vs. saline-treated controls). h[Gly(2)]GLP-2 significantly reduced cytokine induction, bacteremia, and the percentage of positive splenic and hepatic bacterial cultures (P < 0.05). h[Gly(2)]GLP-2 enhanced epithelial proliferation (P < 0.05 for increased crypt cell proliferation in h[Gly(2)]GLP-2- vs. saline-treated mice after indomethacin) and reduced apoptosis in the crypt compartment (P < 0.02). These observations demonstrate that a human GLP-2 analog exerts multiple complementary actions that serve to preserve the integrity of the mucosal epithelium in experimental gastrointestinal injury in vivo.
Boushey
R P
RP
Department of Medicine, The Toronto General Hospital, University of Toronto, Toronto, Canada M5G2C4.
Yusta
B
B
Drucker
D J
DJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004751:Enteritis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality*; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D005934:Glucagon / Q000502:physiology; D006801:Humans; D007082:Ileum / Q000737:chemistry / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007213:Indomethacin; D036341:Intercellular Signaling Peptides and Proteins; D007583:Jejunum / Q000737:chemistry / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016019:Survival Analysis
C117499:(glycyl-glycyl)GLP-2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D018809:Proliferating Cell Nuclear Antigen; D005934:Glucagon; D007213:Indomethacin