Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats.
Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats.
复制标题
DOI：
10.1152/ajpendo.00453.2011
复制
发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Tienian Zhu;Ruijing Zhao;Lizhong Zhang;M. Bernier;Jiankun Liu
中科院分区：
文献类型：
--
作者：
Tienian Zhu;Ruijing Zhao;Lizhong Zhang;M. Bernier;Jiankun Liu
本研究的目的是研究吡咯烷二硫代氨基甲酸酯（PDTC）对2型糖尿病大鼠肝糖原合成和FoxO 1转录活性的影响，并探讨其作用机制。本实验观察了正常饮食（NC）、高脂饮食（HFD）诱导的胰岛素抵抗（IR）大鼠（DM）和PDTC干预DM大鼠（DM + PDTC）1周后的空腹血糖和糖原沉积，以及肝脏中与糖尿病发生相关的两个关键基因的表达。通过Western blot评估禁食大鼠肝脏提取物中Akt、GSK-3β和FoxO 1的磷酸化，而进行间接免疫荧光染色以确定FoxO 1的细胞分布。DM组大鼠空腹血糖明显升高，肝糖原含量明显降低。糖尿病大鼠肝脏Akt/GSK-3β通路的激活和FoxO 1的失活磷酸化明显降低（P < 0.01）。相比之下，PDTC治疗保护DM大鼠免受高空腹血糖和肝糖原沉积损失。PDTC还引起糖尿病大鼠肝脏中Akt/GSK-3β信号传导的增加以及随后FoxO 1的失活和核输出，这转化为两个FoxO 1靶基因磷酸烯醇式丙酮酸羧激酶和葡萄糖-6-磷酸酶的表达显著降低。这项研究表明，PDTC增强肝糖原的合成，而它降低FoxO 1的转录活性在DM大鼠。
The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC) on hepatic glycogen synthesis and FoxO1 transcriptional activity in type 2 diabetic rats and the mechanism underlying these effects. Fasting blood glucose and glycogen deposition, together with expressions of two key genes related to gluconeogenesis, were studied in the liver of rats fed a normal diet (NC), high-fat diet (HFD)-induced insulin-resistant rats made type 2 diabetic by a single intraperitoneal injection of streptozotocin (DM), and a DM with intervention of PDTC (DM + PDTC) for 1 wk. The phosphorylation of Akt, GSK-3β, and FoxO1 was assessed in liver extracts of fasted rats by Western blot, whereas indirect immunofluorescence staining was performed to determine the cellular distribution of FoxO1. The DM rats exhibited obvious increases in fasting blood glucose as well as decreased hepatic glycogen content compared with the NC group. Activation of the Akt/GSK-3β pathway and inactivating phosphorylation of FoxO1 were reduced greatly in DM rat livers (P < 0.01). By contrast, PDTC treatment protected DM rats against high fasting blood glucose and hepatic glycogen deposition loss. PDTC also elicited an increase in Akt/GSK-3β signaling and subsequent inactivation and nuclear export of FoxO1 in DM rat livers, which translated into a significant reduction in the expression of two FoxO1 target genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. This study suggests that PDTC enhances hepatic glycogen synthesis, whereas it reduces FoxO1 transcriptional activity in DM rats.