Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system.
The glucose-6-phosphatase (G-6-Pase) system catalyzes the terminal enzymatic step of gluconeogenesis and glycogenolysis. Inhibition of the G-6-Pase system in the liver is expected to result in a reduction of hepatic glucose production irrespective of the relative contribution of gluconeogenesis or glycogenolysis to hepatic glucose output. In isolated perfused rat liver, S-3483, a derivative of chlorogenic acid, produced concentration-dependent inhibition of gluconeogenesis and glycogenolysis 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 gluconeogenesis, intravenous infusion of S-3483 resulted in a constant reduction of blood glucose levels. Intrahepatic concentrations of glucose-6-phosphate (G-6-P) and glycogen were significantly increased at the end of both in vivo studies. In contrast, lowering of blood glucose in starved rats by 3-mercaptopicolinic acid was accompanied by a reduction of G-6-P and glycogen. Our results demonstrate for the first time in vivo a pharmacologically induced suppression of hepatic G-6-P activity with subsequent changes in blood glucose levels.
Herling
A W
AW
Hoechst Marion Roussel Deutschland GmbH, Frankfurt am Main, Germany.
Burger
H J
HJ
Schwab
D
D
Hemmerle
H
H
Below
P
P
Schubert
G
G
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D010848:Picolinic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D001786:Blood Glucose; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D010848:Picolinic Acids; C113180:S 3483; D019298:Glucose-6-Phosphate; C008363:3-mercaptopicolinic acid; D006003:Glycogen; D005952:Glucose-6-Phosphatase