title: Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia.
abstract: 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.
authors.affiliation: Lawson Research Institute, St. Joseph's Health Centre, London, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Petrik
authors.forename: J M
authors.initials: JM
authors.lastname: Pell
authors.forename: E
authors.initials: E
authors.lastname: Arany
authors.forename: T J
authors.initials: TJ
authors.lastname: McDonald
authors.forename: W L
authors.initials: WL
authors.lastname: Dean
authors.forename: W
authors.initials: W
authors.lastname: Reik
authors.forename: D J
authors.initials: DJ
authors.lastname: Hill
mesh_terms: D000818:Animals; D017209:Apoptosis; D015870:Gene Expression; D006965:Hyperplasia; D017403:In Situ Hybridization; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000032:analysis; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000032:analysis; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000032:analysis; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II