Effect of glucopyranosylidene-spiro-thiohydantoin on glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats
Effect of glucopyranosylidene-spiro-thiohydantoin on glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats
复制标题
DOI：
10.3892/mmr.2011.464
复制
发表时间：
2011-05-01
影响因子：
3.4
通讯作者：
Gergely, Pal
中科院分区：
文献类型：
--
作者：
Docsa, Tibor;Czifrak, Katalin;Gergely, Pal
肝糖原的主要作用是为血液循环提供葡萄糖，以维持正常的血糖水平。在肌肉和肝脏中，糖原的积累和分解受到糖原磷酸化酶和糖原合成酶相互作用的调节。糖原磷酸化酶催化糖原降解的关键步骤，其活性被葡萄糖及其类似物抑制。因此，任何容易获得的糖原磷酸化酶抑制剂都可以作为非胰岛素依赖型或2型糖尿病的潜在治疗方法。肝糖原磷酸化酶已被确定为控制血糖浓度的药物的新靶点。葡聚吡喃-螺环-硫代海因(TH)是最有效的葡萄糖衍生物之一，对肌肉和肝脏糖原磷酸化酶的催化活性均有抑制作用。在这里，我们证明了50MU-TH对Wistar大鼠肝脏提取物中糖原磷酸化酶和合成酶的协同调节，导致合成酶的激活，与对照组动物相比潜伏期缩短。TH还能有效降低链脲佐菌素诱导的糖尿病大鼠的血糖水平，恢复肝糖原含量。此外，静脉注射TH可显著降低Zucker糖尿病肥胖大鼠肝糖原磷酸化酶a的水平，合酶的激活立即启动。
The major role of liver glycogen is to supply glucose to the circulation in order to maintain normal blood glucose levels. In the muscle and liver, the accumulation and breakdown of glycogen are regulated by the reciprocal activities of glycogen phosphorylase and glycogen synthase. Glycogen phosphorylase catalyses the key step of glycogen degradation and its activity is inhibited by glucose and its analogues. Thus, any readily accessible inhibitor of glycogen phosphorylase may serve as a potential therapy for non-insulin-dependent or type 2 diabetes. Hepatic glycogen phosphorylase has been identified as a novel target for drugs that control blood glucose concentration. Glucopyranosylidene-spiro-thiohydantoin (TH) was found to be one of the most potent glucose derivates, inhibiting the catalytic activity of both muscle and liver glycogen phosphorylase. Here, we demonstrated the co-ordinated regulation of glycogen phosphorylase and synthase by 50 mu M TH in liver extracts of Wistar rats, resulting in the activation of synthase by a shortening of the latency compared to control animals. TH was also effective in lowering blood glucose levels and restoring hepatic glycogen content in streptozotocin-induced diabetic rats. Furthermore, intravenous administration of TH to Zucker diabetic fatty rats significantly decreased hepatic glycogen phosphorylase a levels, and the activation of synthase was initiated without any delay.