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Document type:
journal article 
Author(s):
Iakoubov, R; Lauffer, LM; Trivedi, S; Kim, YI; Brubaker, PL 
Title:
Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice. 
Abstract:
Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent intestinotropic hormone that promotes intestinal growth, via increased intestinal proliferation and decreased apoptosis, as well as increases in nutrient absorption and barrier function. The long-acting analog h(Gly(2))GLP-2[1-33] is currently being tested for treatment of short bowel syndrome and Crohn's disease. However, the role of GLP-2 in colon carcinogenesis is controversial. To assess the intestinotropic effects of exogenous and endogenous GLP-2, C57BL6/J mice were injected with 1 microg h(Gly(2))GLP-2[1-33]; 30 or 60 ng hGLP-2[3-33], a GLP-2 receptor antagonist; or PBS (4 wk, twice a day, sc). Chronic h(Gly(2))GLP-2[1-33] increased small intestinal weight/body weight (P< 0.001), villus height (P< 0.001), crypt depth (P< 0.001), and crypt cell proliferation, as measured by expression of the proliferative marker Ki67 (P< 0.05-0.01). In contrast, chronic hGLP-2[3-33] decreased small intestinal weight/body weight (P< 0.05) and colon weight/body weight (P< 0.05). To assess the carcinogenic effects of endogenous and exogenous GLP-2, separate mice were injected with azoxymethane (10 mg/kg, 4 wk, every 7 d, ip), followed by 1.5 microg h(Gly(2))GLP-2[1-33], 30 ng hGLP-2[3-33], or PBS (4 wk, twice a day, sc) 2 or 12 wk thereafter. At 10 or 46 wk after azoxymethane treatment, the numbers of aberrant crypt foci increased with h(Gly(2))GLP-2[1-33] (P< 0.001) and decreased with hGLP-2[3-33] (P< 0.01-0.05) treatment. Furthermore, mucin-depleted aberrant foci, consistent with progressive dysplasia, were almost exclusively present in h(Gly(2))GLP-2[1-33]-treated mice (P< 0.01-0.001). Additionally, adenocarcinomas developed in h(Gly(2))GLP-2[1-33]-treated mice but not in those receiving hGLP-2[3-33] or PBS. Taken together, these studies indicate that chronic treatment with GLP-2 enhances colon carcinogenesis, whereas antagonism of the GLP-2 receptor decreases dysplasia, with possible implications for human therapy. 
Journal title abbreviation:
Endocrinology 
Year:
2009 
Journal volume:
150 
Journal issue:
Pages contribution:
4033-43 
Language:
eng 
Print-ISSN:
0013-7227 
TUM Institution:
II. Medizinische Klinik und Poliklinik