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Hoechst Marion Roussel Deutschland GmbH, 65926 Frankfurt am Main, Germany
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 · h1
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.
inhibition of gluconeogenesis; inhibition of glycogenolysis; inhibition of hepatic glucose output; blood glucose reduction
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