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首页> 外文期刊>American Journal of Physiology >Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system.
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Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system.

机译：新型肝糖6磷酸酶抑制剂的药效学特征。

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摘要

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.
机译：葡萄糖-6-磷酸酶（G-6-Pase）系统催化糖异生和糖原分解的最终酶促步骤。不管肝糖异生或糖原分解对肝葡萄糖输出的相对贡献如何，预期肝脏中G-6-Pase系统的抑制都会导致肝葡萄糖生成的减少。在分离的灌注大鼠肝脏中，绿原酸的衍生物S-3483在相似的浓度范围内产生了对糖异生和糖原分解的浓度依赖性抑制。在饲喂的大鼠中，胰高血糖素诱导的糖原分解作用导致近2小时的高血糖。静脉输注50 mg kg-1 h-1 S-3483可以防止血糖过高，进而导致血糖​​进一步降低。在主要通过糖异生来维持血糖正常的24小时饥饿的大鼠中，静脉输注S-3483导致血糖水平不断降低。在两项体内研究结束时，肝内葡萄糖6-磷酸（G-6-P）和糖原的浓度均显着增加。相反，饥饿的大鼠中3-巯基亚油酸的血糖降低伴随着G-6-P和糖原的降低。我们的结果首次证明了体内药理学诱导的对肝G-6-P活性的抑制以及随后血糖水平的变化。

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