Regulation of rat liver glucokinase activity in vivo: Predominant role of hepatic cyclic AMP and glucocorticoids

Abstract

The role of insulin, glucocorticoids, and hepatic cyclic AMP in the regulation of the activity of rat liver glucokinase was investigated in vivo. The following results were found: (i) Refeeding of starved rats with glucose or injection of diabetic animals with insulin resulted in a dramatic increase in the concentration of serum insulin and a decrease in the concentration of hepatic cyclic AMP followed by a marked rise in the glucokinase activity. While refeeding with protein or fat also led to a drastic rise in the level of serum insulin, the hepatic cyclic AMP concentration remained unchanged as did glucokinase activity, (ii) Feeding of rats with a carbohydrate-rich, protein-free diet had previously been shown to be characterized by very low concentrations of serum insulin and hepatic cyclic AMP (1). Subsequent starvation did not alter the concentrations of insulin, but gradually increased the level of hepatic cyclic AMP. This was followed by a decrease in the highly elevated glucokinase activity, (iii) Refeeding of adrenalectomized, starved rats with glucose resulted in an impaired response of serum insulin and only a slight elevation of glucokinase activity. Injection of insulin in these animals, which led to similar concentrations of the hormone to intact rats refed glucose, did not accelerate the rise in glucokinase activity. Restoration of glucocorticoids prior to refeeding with glucose resulted in an increase in glucokinase activity, identical to that observed in intact controls, while this steroid per se had no effect on enzyme activity. Since under all conditions examined there was a close inverse correlation between the hepatic cyclic AMP concentration and glucokinase activity, but not between the insulin level and the enzyme activity, it is concluded that hepatic cyclic AMP and not serum insulin predominantly regulates the activity of glucokinase in rat liver. It is suggested that glucocorticoids exert a “permissive” action on glucokinase induction.