OVEREXPRESSION OF BOVINE GROWTH-HORMONE IN TRANSGENIC MICE IS ASSOCIATED WITH CHANGES IN HEPATIC INSULIN-RECEPTORS AND IN THEIR KINASE-ACTIVITY

Transgenic mice expressing a hybrid gene produced by linking the promo ter regulatory region of phosphoenolpyruvate carboxykinase (PEPCK) gen e to the bovine growth hormone (bGH) gene, were used to investigate th e effects of GH on insulin binding and insulin dependent tyrosine kina se activity of hepatic insulin receptors. Transgenic mice had normal l evels of blood glucose, despite hyperinsulinemia, indicating that thes e animals were insulin resistant. The number of insulin receptors in t he liver of transgenic mice was significantly decreased in both the pa rticulate fraction (25%) and the solubilized membranes (40%) indicatin g that expressed (functional) and non-expressed (cryptic) receptors we re affected. Scatchard analysis of competitive binding curves for insu lin indicated that the affinity of the receptor did not differ between transgenic and normal mice. Insulin dependent tyrosine kinase activit y in insulin receptors partially purified by wheat germ agglutin (WGA) agarose chromatography from solubilized liver membranes, was measured . The stimulatory action of insulin on phosphorylation of the syntheti c substrate (a copolymer Glu-Tyr, 4:1) was increased 100% in transgeni c, as compared to normal mice, using the same binding activity. Since transgenic mice are hyperinsulinemic, it is likely that the decreased insulin binding in this group reflects down regulation of the expresse d and non-expressed insulin receptors, and the increased kinase activi ty represents a compensatory mechanism. We conclude that alterations i n the insulin receptor number and in the tyrosine kinase activity deve lop in response to changes in insulin levels. Thus, insulin resistance detected in the liver of transgenic mice overexpressing GH may be due to post receptor defects.