Iakoubov Roman, Lauffer Lina M, Trivedi Shivangi, Kim Young-In J, Brubaker Patricia L
Departments of Physiology, University of Toronto, Toronto, Ontario, Canada.
Endocrinology. 2009 Sep;150(9):4033-43. doi: 10.1210/en.2009-0295. Epub 2009 Jun 4.
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.
胰高血糖素样肽-2（GLP-2）是一种营养依赖性肠促激素，通过增加肠道增殖、减少细胞凋亡，以及增强营养吸收和屏障功能来促进肠道生长。长效类似物h(Gly(2))GLP-2[1-33]目前正在进行治疗短肠综合征和克罗恩病的试验。然而，GLP-2在结肠癌发生中的作用存在争议。为了评估外源性和内源性GLP-2的肠促作用，给C57BL6/J小鼠注射1微克h(Gly(2))GLP-2[1-33]；30或60纳克hGLP-2[3-33]（一种GLP-2受体拮抗剂）；或磷酸盐缓冲液（4周，每天两次，皮下注射）。慢性给予h(Gly(2))GLP-2[1-33]可增加小肠重量/体重（P<0.001）、绒毛高度（P<0.001）、隐窝深度（P<0.001），以及隐窝细胞增殖，通过增殖标志物Ki67的表达来衡量（P<0.05-0.01）。相比之下，慢性给予hGLP-2[3-33]可降低小肠重量/体重（P<0.05）和结肠重量/体重（P<0.05）。为了评估内源性和外源性GLP-2的致癌作用，给另一组小鼠注射偶氮甲烷（10毫克/千克，4周，每7天一次，腹腔注射），随后在2周或12周后分别注射1.5微克h(Gly(2))GLP-2[1-33]、30纳克hGLP-2[3-33]或磷酸盐缓冲液（4周，每天两次，皮下注射）。在偶氮甲烷处理后的10周或46周，异常隐窝灶的数量在h(Gly(2))GLP-2[1-33]处理组中增加（P<0.001），而在hGLP-2[3-33]处理组中减少（P<0.01-0.05）。此外，与进行性发育异常一致的黏液缺失异常灶几乎仅在h(Gly(2))GLP-2[1-33]处理的小鼠中出现（P<0.01-0.001）。此外，h(Gly(2))GLP-2[1-33]处理的小鼠发生了腺癌，而接受hGLP-2[3-33]或磷酸盐缓冲液处理的小鼠未发生。综上所述，这些研究表明，GLP-2的慢性治疗会增强结肠癌的发生，而GLP-2受体的拮抗作用会减少发育异常，这可能对人类治疗有一定意义。
