Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice

Background & Aims: Our understanding of the intestinotropic actions of glucagon-like peptide-2 (GLP-2)1-33 is based on pharmacologic studies involving exogenous administration. However, the physiologic role of GLP-2 in mucosal growth and adaptation to nutritional stimulation remains poorly understood. Methods: The properties of GLP-23-33, a GLP-21-33 metabolite, were determined in baby-hamster kidney cells transfected with the mouse GLP-2 receptor complementary DNA and in isolated murine intestinal muscle strips. To investigate the role of endogenous GLP-21-33 in gut adaptation, GLP-23-33 was administered to mice that were re-fed for 24 hours after 24 hours of fasting, and the small intestine was analyzed. GLP-23-33 also was injected into rats for analysis of circulating GLP-21-33 levels. Results: GLP-23-33 antagonized the actions of GLP-21-33 in vitro and ex vivo. Fasting mice exhibited small intestinal atrophy (37% ± 1% decrease in small intestinal weight, 19% ± 2% decrease in crypt-villus height, and 99% ± 35% increase in villus apoptosis, P < .05-.01). Adaptive growth in re-fed mice restored all these parameters, as well as crypt-cell proliferation, to normal control levels (P < .05 vs. fasting); these adaptive changes were prevented partially or completely by co-administration of GLP-23-33 to refeeding mice (by 32% ± 19% to 103% ± 15%, P < .05-.01 vs re-fed mice). Exogenous GLP-23-33 did not affect endogenous GLP-21-33 levels. Conclusions: These data show that endogenous GLP-2 regulates the intestinotropic response in re-fed mice through modulation of crypt-cell proliferation and villus apoptosis. GLP-2 is therefore a physiologic regulator of the dynamic adaptation of the gut mucosal epithelium in response to luminal nutrients.