Overexpression of the c-Myc transcription factor in liver induces glucose uptake and utilization. Here we examined the effects of c- myc overexpression on the expression of hepatocyte-specific transcription factor genes which regulate the expression of genes controlling hepatic metabolism. At 4 months after streptozotocin (STZ) treatment, most diabetic control mice were highly hyperglycaemic and died, whereas in STZ-treated transgenic mice hyperglycaemia was markedly lower, the serum levels of beta-hydroxybutyrate, triacylglycerols and non-esterified fatty acids were normal, and they had greater viability in the absence of insulin. Furthermore, long-term STZ-treated transgenic mice showed similar glucose utilization and storage to healthy controls. This was consistent with the expression of glycolytic genes becoming normalized. In addition, restoration of gene expression of the transcription factor, sterol receptor element binding protein 1c, was observed in the livers of these transgenic mice. Further, in STZ-treated transgenic mice the expression of genes involved in the control of gluconeogenesis (phosphoenolpyruvate carbokykinase), ketogenesis (3-hydroxy-3-methylglutaryl-CoA synthase) and energy metabolism (uncoupling protein 2) had returned to normal. These findings were correlated with decreased expression of genes encoding the transcription factors hepatocyte nuclear factor 3gamma, peroxisome proliferator-activated receptor alpha and retinoid X receptor. These results indicate that c- myc overexpression may counteract diabetic changes by controlling hepatic glucose metabolism, both directly by altering the expression of metabolic genes and through the expression of key transcription factor genes.