PREVENTION OF DIABETIC ALTERATIONS IN TRANSGENIC MICE OVEREXPRESSING MYC IN THE LIVER

Recent studies have demonstrated that the overexpression of the c-myc gene in the liver of transgenic mice leads to an increase in both util ization and accumulation of glucose in the liver, suggesting that c-My c transcription factor is involved in the control of liver carbohydrat e metabolism in vivo. To determine whether the increase in c-Myc might control glucose homeostasis, an intraperitoneal glucose tolerance tes t was performed, Transgenic mice showed lower levels of blood glucose than control animals, indicating that the overexpression of c-Myc led to an increase of blood glucose disposal by the liver, Thus, the incre ase in c-Myc might counteract diabetic hyperglycemia. In contrast to c ontrol mice, transgenic mice treated with streptozotocin showed normal ization of concentrations of blood glucose, ketone bodies, triacylglyc erols and free fatty acids in the absence of insulin, These findings r esulted from the normalization of liver metabolism in these animals, W hile low glucokinase activity was detected in the liver of diabetic co ntrol mice, high levels of both glucokinase mRNA and enzyme activity w ere noted in the liver of streptozotocin-treated transgenic mice, whic h led to an increase in intracellular levels of glucose 6-phosphate an d glycogen, The liver of these mice also showed an Increase in pyruvat e kinase activity and lactate production, Furthermore, normalization o f both the expression of genes involved in the control of gluconeogene sis and ketogenesis and the production of glucose and ketone bodies wa s observed in streptozotocin-treated transgenic mice. Thus, these resu lts suggested that c-Myc counteracted diabetic alterations through its ability to induce hepatic glucose uptake and utilization and to block the activation of gluconeogenesis and ketogenesis.