Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets

In rats, a proportion of pancreatic beta-cells are deleted by apoptosis in the second week of postnatal life and replaced by endocrine cell neogenesis from pancreatic ductal epithelium. This coincides with a reduction in panc reatic insulin-like growth factor II (IGF-II) expression, and IGF-II has be en shown to act as a beta-cell survival factor in vitro. To examine whether IGF-II regulates beta-cell apoptosis in vivo, an IGF-II transgenic mouse m odel was used in which mouse IGF-II is overexpressed in skin, gut, and uter us driven by a keratin promoter, so that circulating IGF-II is retained pos tnatally. Mice were killed between postnatal days 7 and 26, and the pancrea s was examined histologically. Apoptotic cells were visualized by the termi nal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling method , and proliferating cells were examined by immunohistochemistry for prolife rating cell nuclear antigen. In nontransgenic mice, serum IGF-II was absent by 26 days, but mean (+/-SEM) values were 45 +/- 9 ng/ml (n = 5) in transg enic animals. A 2- to 3-fold rise in islet cell apoptosis was seen in norma l animals between days 11 and 16, but this was substantially decreased in I GF-II transgenic mice (day 11; control, 12 +/- 1%; transgenic, 6 +/- 1%; P < 0.01; n = 5). Consequently, islets from IGF-II transgenic mice had a sign ificantly greater mean area from days 11-16, but the proportions of beta- a nd alpha-cells and circulating insulin levels were not changed. Islet cell DNA synthesis was increased in transgenic mice on days 13 and 16. The total islet number per section did not alter. The results show that a persistent presence of circulating IGF-II postnatally alters endocrine pancreatic ont ogeny in the mouse and largely prevents the wave of developmental apoptosis that precipitates beta-cell turnover in neonatal life.