Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver

To study the role of glucokinase (GK) in the control of glucose metabolism in the liver, transgenic mice were generated in which GK was overexpressed under control of the P-enolpyruvate carboxykinase gene promoter, Whereas the expression of the GK gene in starved control mice was blocked, this promoter was able to direct the expression of the enzyme to the liver of starved transgenic mice, Furthermore, starved transgenic mice showed levels of GK activity fourfold higher than those of starved control and similar to those of fed control, This activation of GEC led to an increase in the intracellular concentration. of glucose 6-phosphate, which was also related ito an induction of glycogen accumulation, In addition, L-pyruvate kinase (L-PK) activity increased in transgenic mice, which when starved showed similar levels of activity to control fed mice, The induction of L-PK caused an increase in the hepatic lactate concentration, Furthermore, hepatocytes in primary culture from transgenic mice incubated with 20 mM glucose produced levels of lactate threefold higher than controls, but no difference was noted when the hepatocytes from control and transgenic mice were incubated with 2 mM glucose. These results demonstrated in vivo that the activation of GK is a rate-limiting step in the induction of glycolysis and glycogen synthesis. These changes in liver glucose metabolism led to a marked reduction in blood glucose (30%) and insulin (40%) concentrations. Furthermore, transgenic mice showed lower levels of blood glucose after an intraperitoneal glucose tolerance test, indicating that GK overexpression caused an increase in blood glucose disposal by the Liver, All these findings show the key role of liver GK in the control of whole-body glucose homeostasis.