Details

Autor(en) / Beteiligte

• Iakoubov, Roman
• Lauffer, Lina M
• Trivedi, Shivangi
• Kim, Young-In J
• Brubaker, Patricia L

Titel

Carcinogenic Effects of Exogenous and Endogenous Glucagon-Like Peptide-2 in Azoxymethane-Treated Mice

Ist Teil von

• Endocrinology (Philadelphia), 2009-09, Vol.150 (9), p.4033-4043

Ort / Verlag

Chevy Chase, MD: Endocrine Society

Erscheinungsjahr

2009

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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(Gly2)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 1μg h(Gly2)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(Gly2)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 μg h(Gly2)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(Gly2)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(Gly2)GLP-2[1-33]-treated mice (P < 0.01–0.001). Additionally, adenocarcinomas developed in h(Gly2)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. Colon dysplasia is increased by the intestinal hormone GLP-2, and decreased by antagonism of the GLP-2 receptor in azoxymethane-treated mice.