Direct regulation of glucose and not insulin on hepatic hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1.
Direct regulation of glucose and not insulin on hepatic hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1.
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直接调节葡萄糖而不是胰岛素对肝己糖 6-磷酸脱氢酶和 11β-羟基类固醇脱氢酶 1 型
DOI：
10.1016/j.mce.2010.12.010
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发表时间：
2011-02-10
影响因子：
4.1
通讯作者：
Liu, Yanjun
中科院分区：
文献类型：
--
作者：
Fan, Zheng;Du, Hongwei;Zhang, Ming;Meng, Zhaojie;Chen, Li;Liu, Yanjun
关键词：
肝脏糖异生异常对2型糖尿病患者的空腹和非空腹高血糖有显着影响。11β-羟基类固醇脱氢酶1（11β-hydroxysteroid dehydrogenase type 1，11β-HSD 1）通过糖皮质激素受体（glucocorticoid receptor，GR）介导的组织糖皮质激素作用的放大来调节关键的肝促凋亡酶包括磷酸烯醇丙酮酸羧激酶（phosphoenolpyruvate carboxykinase，PEPCK）和葡萄糖-6-磷酸酶（glucose-6-phosphatase，G6-phosphatase，G6-phosphatase，G6-phosphatase，G6-phosphatase），并且关键地依赖于产生NADPH的己糖-6-磷酸脱氢酶（hexose-6-phosphate dehydrogenase，H6-PDH）系统。在此，我们观察到与禁食状态相比，非禁食状态下正常和糖尿病大鼠肝脏中H6 PDH和11β-HSD 1的表达均增加，且非禁食糖尿病组在四个实验组中最高。此外，原代肝细胞与增加的葡萄糖孵育引起H6 PDH、11β-HSD 1、GR、PEPCK和G6 β表达的剂量依赖性增加。葡萄糖-6-磷酸（G6 P）对肝细胞内H6 PDH和11β-HSD 1的表达有正性调节作用。此外，高糖条件下不同剂量胰岛素处理的原代肝细胞H6 PDH和11β-HSD 1表达均发生变化，而低糖条件下胰岛素处理的原代肝细胞H6 PDH和11β-HSD 1表达无明显变化。这些结果表明，葡萄糖而不是胰岛素直接调节H6 PDH和11β-HSD 1，抑制这两种酶可被认为是治疗2型糖尿病的有效靶点。
Abnormal hepatic gluconeogenesis contributes significantly to both fasting and non-fasting hyperglycemia of patients with type 2 diabetes. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates the key hepatic gluconeogenic enzymes including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) through the amplification of glucocorticoid receptor (GR) – mediated tissue glucocorticoid action, and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH) – generating NADPH system. Here, we observed that compared with fasting state, H6PDH and 11β-HSD1 expression in livers were all increased under non-fasting state in both normal and diabetic rats, and the non-fasting diabetic group was the highest among the four experimental groups. Moreover, incubation of primary hepatocytes with increasing glucose caused dose-dependent increases in H6PDH, 11β-HSD1, GR, PEPCK and G6Pase expression. Also, glucose-6-phosphate (G6P) had a positive regulation on H6PDH and 11β-HSD1 in hepatocytes. In addition, primary hepatocytes treated with different doses of insulin in high glucose induced alteration of H6PDH and 11β-HSD1 while in low glucose there was no significant effect. These findings suggest that glucose instead of insulin directly regulates H6PDH and 11β-HSD1 and suppression of the two enzymes could be considered as an effective target for the treatment of type 2 diabetes.
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影响因子：
7.7
作者：
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通讯作者：
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影响因子：
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