INTERACTIONS OF INSULIN-LIKE-GROWTH-FACTOR (IGF)-II AND GROWTH-HORMONE IN-VIVO - CIRCULATING LEVELS OF IGF-I AND IGF-BINDING PROTEINS IN TRANSGENIC MICE

To study interactions between insulin-like growth factor-II (IGF-II) a nd growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harb ouring both transgenes (IB), the IGF-II transgene (I) or the bGH trans gene (B), and non-transgenic littermates (C) were obtained. Blood samp les were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to s timulate PEPCK promoter-controlled transgene expression, Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and in creased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/m l. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice, Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IG F-LT increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in I mice. Circulating IGF-I concentrations were about twofold (P < 0. 001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were ma intained on the standard diet. The high-protein diet did not change ci rculating ICE-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001), Consequently, after PEPCK-IGF-II transgene e xpression was stimulated, serum ICE-I concentrations were significantl y (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF- binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained o n the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be g reater in B and IB than in C and I mice, but these differences were mo stly not significant. IGFBP-4 concentrations were significantly (P < 0 .001) increased by GK overproduction in B and IB mice. Our data sugges t that the reduction in circulating TGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH -dependent IGF-I production. Effects of GH overproduction on serum IGF BP-2 concentrations depend on dietary factors and may be both inhibito ry and stimulatory.