Enhanced Growth of Small Bowel in Transgenic Mice Expressing Human Insulin-Like Growth Factor

Abstract

Insulin-like growth factor 1 (IGF-1) plays an important role in the regulation of intestinal growth and maturation, whereas the direct effects of growth hormone (GH) on intestinal growth are less clear. In this study the authors utilize a transgenic mouse model to assess the extent to which longterm excess of IGF-1 in a background of GH deficiency stimulates small bowel growth.

IGF-1 transgenic mice that overexpress an IGF-1 transgene driven by the mouse metallothionein I promotor were compared with wild-type littermates and GH transgenic mice. The IGF-1 transgenics showed elevation of circulating IGF-1, undetectable levels of plasma GH, and a decrease in pituitary GH messenger RNA (mRNA) caused by negative feedback effects of IGF-1 excess. Growth of small bowel, abundance and localization of mRNAs for the IGF-1 transgene, and IGF binding protein 3 (IGFBP-3) were assayed to determine whether enterotrophic effects of excess IGF-1 correlate with local overexpression of IGF-1 in small bowel.

Small bowel length and mass were greater in IGF-1 transgenic than in wild-type mice. Villus height, crypt depth, and crypt cell mitoses were greater in IGF-1 transgenics than wild-type mice. Jejunal dissacharidase activities were not different among the IGF-1 transgenics and wild-type mice. The IGF-1 transgene was expressed strongly in villus epithelial cells and at much lower, but significant levels in crypt epithelial cells, lamina propria, and smooth muscle layers. IGFBP-3 was strongly expressed and localized in the lamina propria.Regional expression of IGF-1 and IGFBP-3 correlated with the increase in mucosal mass in IGF-I transgenics.

Effects of IGF-I overexpression on intestinal length and mucosal mass were similar to effects of GH overexpression, although IGF-I transgenics showed greater small bowel growth relative to somatic growth compared with GH transgenics. Excess of IGF-I increased crypt cell proliferation, whereas excess of GH did not increase crypt cell proliferation but did stimulate jejunal sucrase activity. These observations suggest that GH has greater differentiative actions, whereas IGF-I exerts primarily mitogenic actions in small bowel.