GLUCOSE-METABOLISM IN TRANSGENIC MICE CONTAINING A CHIMERIC P-ENOLPYRUVATE CARBOXYKINASE BOVINE GROWTH-HORMONE GENE

Transgenic mice, containing the chimeric gene obtained by linking the promoter-regulatory region of P-enolpyruvate carboxykinase (PEPCK) gen e to the bovine growth hormone structural gene (bGH), were used to inv estigate the long-term effects of bGH on glucose metabolism. Expressio n of the PEPCK/bGH gene was markedly enhanced by feeding a diet high i n protein and inhibited by a high carbohydrate diet. All transgenic mi ce had normal levels of blood glucose but were hyperinsulinemic, indic ating that they were insulin resistant. The glycogen synthase activity ratios in the muscle and liver of transgenic mice were lower than not ed for control animals, and remained unchanged in liver after feeding a standard high carbohydrate or a high protein diet. Similar effects w ere detected in the activity of glycogen phosphorylase, except that a high carbohydrate diet activated this enzyme in the liver. The activat ion of glycogen phosphorylase in both muscle and liver correlated with the expression of their genes. These animals had a significant conten t of glycogen and glucose 6-phosphate, which was related to the levels of glucokinase mRNA in the liver. The concentration of fructose 2,6-b isphosphate in the liver of all fed transgenic mice was lower than not ed in livers from fed animals. In addition, a decrease in the hepatic expression of the endogenous genes for PEPCK, tyrosine aminotransferas e (TAT), and the glucose transporter GLUT-2 was observed and directly correlated with the expression of bGH. Thus, bGH can control glucose m etabolism in vivo, at least in part, by modifying the expression of se veral genes coding for proteins of importance in carbohydrate metaboli sm. Taken together, these results indicate a state of insulin resistan ce caused by chronic exposure of the animals to an elevated concentrat ion of bGH.