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Increased and Persistent Circulating Insulin-Like Growth Factor II in Neonatal Transgenic Mice Suppresses Developmental Apoptosis in the Pancreatic Islets¹

Lawson Research Institute, St. Joseph’s Health Center (D.J.H., B.S., E.A., S.C.), London, Ontario, Canada N6A 4V2; the Departments of Physiology (D.J.H.), Medicine (D.J.H.), and Pediatrics (D.J.H.), University of Western Ontario, London, Ontario, Canada N6A 5A5; and the Department of Zoology, University of Oxford (S.Z., C.F.G.), Oxford, United Kingdom OX1 3PS

Address all correspondence and requests for reprints to: Dr. D. J. Hill, Lawson Research Institute, St. Joseph’s Health Center, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. E-mail: dhill{at}lri.stjosephs.london.on.ca

In rats, a proportion of pancreatic ß-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 pancreatic insulin-like growth factor II (IGF-II) expression, and IGF-II has been shown to act as a ß-cell survival factor in vitro. To examine whether IGF-II regulates ß-cell apoptosis in vivo, an IGF-II transgenic mouse model was used in which mouse IGF-II is overexpressed in skin, gut, and uterus driven by a keratin promoter, so that circulating IGF-II is retained postnatally. Mice were killed between postnatal days 7 and 26, and the pancreas was examined histologically. Apoptotic cells were visualized by the terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling method, and proliferating cells were examined by immunohistochemistry for proliferating 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 transgenic animals. A 2- to 3-fold rise in islet cell apoptosis was seen in normal animals between days 11 and 16, but this was substantially decreased in IGF-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 significantly greater mean area from days 11–16, but the proportions of ß- and -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 ontogeny in the mouse and largely prevents the wave of developmental apoptosis that precipitates ß-cell turnover in neonatal life.

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