Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia

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 dev elopment of the endocrine pancreas. Fetuses examined on day 19.5-20 of gest ation had significantly elevated circulating levels of IGF-II, compared wit h control mice. The pancreatic islets in transgenic animals were of irregul ar shape and had a mean area five times greater than in controls, whereas t he mean number of islets per tissue section was not altered. The size of in dividual endocrine cells was not altered. Although the islets in animals ex pressing the IGF-II transgene were considerably larger, immuno-histochemist ry for insulin and glucagon showed that the relative proportion of p-cells was significantly less, and that of a-cells was higher. Normal islet morpho logy was disrupted, with a-cells appearing in small groups within the islet s, as well as on the periphery, whereas p-cells were often seen at the edge of the islets. Twice as many islet cells (21.9% vs. 11.4%) were involved i n cell replication, detected by the presence of immunoreactive proliferatin g cell nuclear antigen, in pancreata from transgenic mice vs. controls, whe reas the number of cells undergoing apoptosis was significantly reduced. Ab undant IGF-II messenger RNA was found within the islets of transgenic anima ls by in situ hybridization, and the relative area of islets demonstrating immunoreactive IGF-II was significantly greater. Immunoreactive IGF-I was m uch less abundant and was further reduced in islets of transgenic animals. The area of islets immunopositive for IGF binding protein-a was unaltered. Despite the presence of islet hyperplasia, circulating insulin levels and s erum 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 hyperplasi a while reducing the attrition of islet cells by apoptosis.