Petrik J, Pell J M, Arany E, McDonald T J, Dean W L, Reik W, Hill D J
Lawson Research Institute, St. Joseph's Health Centre, London, Ontario, Canada.
Endocrinology. 1999 May;140(5):2353-63. doi: 10.1210/endo.140.5.6732.
We have used an insulin-like growth factor (IGF)-II transgenic mouse model in which mouse IGF-II is widely overexpressed, resulting in increased fetal size and selective organ overgrowth, to investigate the effects on the development of the endocrine pancreas. Fetuses examined on day 19.5-20 of gestation had significantly elevated circulating levels of IGF-II, compared with control mice. The pancreatic islets in transgenic animals were of irregular shape and had a mean area five times greater than in controls, whereas the mean number of islets per tissue section was not altered. The size of individual endocrine cells was not altered. Although the islets in animals expressing the IGF-II transgene were considerably larger, immunohistochemistry for insulin and glucagon showed that the relative proportion of beta-cells was significantly less, and that of alpha-cells was higher. Normal islet morphology was disrupted, with alpha-cells appearing in small groups within the islets, as well as on the periphery, whereas beta-cells were often seen at the edge of the islets. Twice as many islet cells (21.9% vs. 11.4%) were involved in cell replication, detected by the presence of immunoreactive proliferating cell nuclear antigen, in pancreata from transgenic mice vs. controls, whereas the number of cells undergoing apoptosis was significantly reduced. Abundant IGF-II messenger RNAwas found within the islets of transgenic animals by in situ hybridization, and the relative area of islets demonstrating immunoreactive IGF-II was significantly greater. Immunoreactive IGF-I was much less abundant and was further reduced in islets of transgenic animals. The area of islets immunopositive for IGF binding protein-2 was unaltered. Despite the presence of islet hyperplasia, circulating insulin levels and serum glucose levels were not significantly different between transgenic and control mice. These results show that an overexpression of IGF-II in fetal life has a profound effect on islet morphology and causes islet hyperplasia while reducing the attrition of islet cells by apoptosis.
我们使用了一种胰岛素样生长因子（IGF）-II转基因小鼠模型，其中小鼠IGF-II广泛过度表达，导致胎儿体型增大和选择性器官过度生长，以研究其对内分泌胰腺发育的影响。与对照小鼠相比，在妊娠第19.5 - 20天检查的胎儿循环中IGF-II水平显著升高。转基因动物的胰岛形状不规则，平均面积比对照大五倍，而每个组织切片的胰岛平均数量未改变。单个内分泌细胞的大小未改变。尽管表达IGF-II转基因的动物的胰岛明显更大，但胰岛素和胰高血糖素的免疫组织化学显示β细胞的相对比例显著降低，而α细胞的比例更高。正常的胰岛形态被破坏，α细胞出现在胰岛内的小群体中以及周边，而β细胞经常出现在胰岛边缘。通过免疫反应性增殖细胞核抗原的存在检测到，转基因小鼠胰腺中参与细胞复制的胰岛细胞数量是对照小鼠的两倍（21.9%对11.4%），而发生凋亡的细胞数量显著减少。通过原位杂交在转基因动物的胰岛内发现了丰富的IGF-II信使核糖核酸，显示免疫反应性IGF-II的胰岛相对面积显著更大。免疫反应性IGF-I含量少得多，并且在转基因动物的胰岛中进一步降低。对IGF结合蛋白-2呈免疫阳性的胰岛面积未改变。尽管存在胰岛增生，但转基因小鼠和对照小鼠之间的循环胰岛素水平和血清葡萄糖水平没有显著差异。这些结果表明，胎儿期IGF-II的过度表达对胰岛形态有深远影响，导致胰岛增生，同时减少胰岛细胞因凋亡而产生的损耗。
