Glucose regulates in vivo glucose-6-phosphatase gene expression in the liver of diabetic rats

Overproduction of glucose by the liver is the major cause of fasting hyperglycemia in both insulin-dependent and non-insulin-dependent diabetes mellitus. The distal enzymatic step in the process of glucose output is catalyzed by the glucose-6-phosphatase complex. We show here that 90% partially pancreatectomized diabetic rats have a >5-fold increase in the messenger RNA and a 3-4-fold increase in the protein level of the catalytic subunit of glucose-6-phosphatase in the liver. Normalization of the plasma glucose concentration in diabetic rats with either insulin or the glycosuric agent phlorizin normalized the hepatic glucose-6-phosphatase messenger RNA and protein within ~8 h. Conversely, phlorizin failed to decrease hepatic glucose-6-phosphatase gene expression in diabetic rats when the fall in the plasma glucose concentration was prevented by glucose infusion. These data indicate that in vivo gene expression of glucose-6-phosphatase in the diabetic liver is regulated by glucose independently from insulin, and thus prolonged hyperglycemia may result in overproduction of glucose via increased expression of this protein.