PHARMACODYNAMIC PROFILE OF A NOVEL INHIBITOR OF THE HEPATIC GLUCOSE-6-PHOSPHATASE SYSTEM

The glucose-6-phosphatase (G-6-Pase) system catalyzes the terminal enz ymatic step of gluconeogenesis and glycogenolysis. Inhibition of the G -6-Pase system in the liver is expected to result in a reduction of he patic glucose production irrespective of the relative contribution of gluconeogenesis or glycogenolysis to hepatic glucose output. In isolat ed perfused rat liver, S-3483, a derivative of chlorogenic acid, produ ced concentration-dependent inhibition of gluconeogenesis and glycogen olysis in a similar concentration range. In fed rats, glucagon-induced glycogenolysis resulted in hyperglycemia for nearly 2 h. Intravenous infusion of 50 mg kg(-1) h(-1) S-3483 prevented the hyperglycemic peak and subsequently caused a further lowering of blood glucose. In 24-h starved rats, in which normoglycemia is maintained predominantly by gl uconeogenesis, intravenous infusion of S-3483 resulted in a constant r eduction of blood glucose levels. Intrahepatic concentrations of gluco se-g-phosphate (G-6-P) and glycogen were significantly increased at th e end of both in vivo studies. In contrast, lowering of blood glucose in starved rats by 3-mercaptopicolinic acid was accompanied by a reduc tion of G-6-P and glycogen. Our results demonstrate for the first time in vivo a pharmacologically induced suppression of hepatic G-6-P acti vity with subsequent changes in blood glucose levels.