Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice
Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice
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DOI：
10.1016/j.regpep.2012.08.016
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发表时间：
2012-11-10
影响因子：
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通讯作者：
Poulsen, Steen Seier
中科院分区：
文献类型：
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作者：
Kissow, Hannelouise;Hartmann, Bolette;Poulsen, Steen Seier
前言：胰高血糖素样肽-1(GLP-1)和胰高血糖素样肽-2(GLP-2)是肠道内分泌细胞摄取营养物质后平行分泌的产物。GLP-1是一种生长素激素，类似物可用于治疗2型糖尿病(T2 DM)。GLP-2是一种肠道生长激素，被证明能促进致癌小鼠结肠腺瘤的生长。这两种多肽都被二肽基肽酶-4(DPP-4)降解为非活性代谢物。因此，DPP-4抑制剂也被用于治疗T2 DM。通过增加内源性GLP-2对肠上皮细胞的暴露，抑制DPP-4可能也可能介导生长并促进肿瘤的发生。我们研究了GLP-1受体激动剂(GLP-1RAS)(利拉鲁肽和埃塞那肽)和DPP-4抑制剂(西格列汀)对健康小鼠肠道生长的影响。我们还研究了利拉鲁肽和西格列汀在致癌物处理的小鼠结肠中的潜在促癌作用。以GLP-2作为阳性对照。方法：在生长研究中，健康CD1小鼠分别给予利拉鲁肽(300mgx2)、艾塞那肽(12.5mgx2)或赋形剂+西格列汀(8mgx2)或水灌胃10~30d。测量肠道重量、横截面积、绒毛高度和隐窝深度。在肿瘤研究中，我们用利拉鲁肽(300mgx2)、Gly2-GLP-2(25mgx2)或赋形剂和西格列汀(8mgx2)皮下注射致癌剂(1，2二甲基肼每周21 mg/kg，共12周)或水灌胃45d。我们计算了异常隐窝病灶(ACF)、粘蛋白耗竭病灶(MDF)和结肠腺瘤。用转GLP-2受体的COS-7细胞检测利拉鲁肽和艾塞那肽对受体的激活作用。结果：在10天的实验中，利拉鲁肽组的相对小肠重量增加了56%(P
Introduction: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth hormone and is shown to promote growth of colonic adenomas in carcinogen treated mice. Both peptides are degraded by dipeptidyl peptidase-4 (DPP-4) into inactive metabolites. DPP-4 inhibitors are therefore also in use for treatment of T2DM. It is possible that DPP-4 inhibition by enhancing the exposure of endogenous GLP-2 to the intestinal epithelia also might mediate growth and promote neoplasia. We investigated the intestinal growth effect of the GLP-1 receptor agonists (GLP-1 RAs) (liraglutide and exenatide) and DPP-4 inhibition (sitagliptin) in healthy mice. We also investigated the potential tumour promoting effect of liraglutide and sitaglitin in the colon of carcinogen treated mice. We used GLP-2 as a positive control.Methods: For the growth study we treated healthy CD1 mice with liraglutide (300 mu g x 2), exenatide (12.5 mu g x 2) or vehicle subcutaneously and sitagliptin (8 mg x 2) or water by oral gavage for 10 or 30 days. We measured intestinal weight, cross sectional area, villus height and crypt depth. For the tumour study we treated carcinogen treated mice (1,2 dimethylhydrazine 21 mg/kg/week for 12 weeks) with liraglutide (300 mu g x 2), Gly2-GLP-2 (25 mu g x 2) or vehicle subcutaneously and sitagliptin (8 mg x 2) or water by oral gavage for 45 days. We counted aberrant crypt foci (ACF), mucin depleted foci (MDF) and adenomas in the colon. Using COS-7 cells transfected with a GLP-2 receptor, we tested if liraglutide or exenatide could activate the receptor.Results: In the 10 days experiment the relative small intestinal weight was increased with 56% in the liraglutide group (p