Aw. Herling et al., PHARMACODYNAMIC PROFILE OF A NOVEL INHIBITOR OF THE HEPATIC GLUCOSE-6-PHOSPHATASE SYSTEM, American journal of physiology: Gastrointestinal and liver physiology, 37(6), 1998, pp. 1087-1093
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.