GdCl3 reduces hyperglycaemia through Akt/FoxO1-induced suppression of hepatic gluconeogenesis in Type 2 diabetic mice
GdCl3 reduces hyperglycaemia through Akt/FoxO1-induced suppression of hepatic gluconeogenesis in Type 2 diabetic mice
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GdCl3 通过 Akt/FoxO1 诱导抑制 2 型糖尿病小鼠的肝糖异生来降低高血糖
DOI：
10.1042/cs20130670
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发表时间：
2014-07-01
期刊：
影响因子：
6
通讯作者：
Chen, Yuanyuan
中科院分区：
文献类型：
--
作者：
Wang, Qian;Wang, Ning;Chen, Yuanyuan
GdCl 3（氯化钆）已被证明可以降低血糖;然而，其潜在机制仍不清楚。肝脏糖异生是维持葡萄糖稳态的重要途径。本研究旨在探讨GdCl 3在肝硬化发生中的作用及其分子机制。通过将C57 BL/6 J小鼠暴露于高脂肪饮食4个月来创建的经典2型糖尿病小鼠模型的动物用GdCl 3或盐水处理。监测体重、血糖和胰岛素敏感性。观察到GdCl 3显著降低血糖水平并改善胰岛素敏感性。丙酮酸耐量试验进一步表明，GdCl 3抑制糖尿病小鼠的血管生成。在GdCl 3处理的小鼠的肝脏中，Pepck（磷酸烯醇丙酮酸羧激酶）和G6 pase（葡萄糖-6-磷酸酶）的表达，这两种酶是肝脏发生中的关键酶，它们的表达显著降低。此外，在肝癌细胞中的实验显示，GdCl 3激活Akt通路以促进FoxO 1（叉头框01）的磷酸化，通过减少PEPCK和G6 β的表达导致肿瘤发生的抑制，并导致细胞葡萄糖的产生减少。在GdCl 3处理的小鼠的肝脏中观察到类似的结果。此外，我们已经表明，氯化钆增强胰岛素的作用，以控制肝葡萄糖的生产。我们的结论是，GdCl 3通过Akt/FoxO 1诱导的抑制肝细胞再生，在2型糖尿病小鼠（体内）和肝癌细胞（体外），表明GdCl 3可能是一个潜在的治疗剂糖尿病降低高血糖症。
GdCl3 (gadolinium chloride) has been shown to reduce blood glucose; however, the underlying mechanism remains unclear. Liver gluconeogenesis is an important pathway involved in the maintenance of glucose homoeostasis. The aim of the present study was to investigate the role of GdCl3 in hepatic gluconeogenesis and explore the precise molecular mechanism. Animals from a classical Type 2 diabetic mouse model, created by exposing C57BL/6J mice to a high-fat diet for 4 months, were treated with GdCl3 or saline. Body weight, blood glucose and insulin sensitivity were monitored. It was observed that GdCl3 significantly reduced blood glucose levels and improved insulin sensitivity. A pyruvate tolerance test showed further that GdCl3 suppressed gluconeogenesis in diabetic mice. In the livers of GdCl3-treated mice, the expression of Pepck (phosphoenolpyruvate carboxykinase) and G6pase (glucose-6-phosphatase), the key enzymes in gluconeogenesis, were dramatically reduced. Furthermore, experiments in hepatocarcinoma cells revealed that GdCl3 activated the Akt pathway to promote the phosphorylation of FoxO1 (forkhead box 01), leading to the suppression of gluconeogenesis by reducing the expression of PEPCK and G6Pase and resulting in decreased cellular production of glucose. Comparable results were observed in the livers of GdCl3-treated mice. In addition, we have shown that GdCl3 augmented the role of insulin to control hepatic glucose production. We conclude that GdCl3 reduces hyperglycaemia via the Akt/FoxO1-induced suppression of hepatic gluconeogenesis, both in Type 2 diabetic mice (in vivo) and in hepatocarcinoma cells (in vitro), suggesting that GdCl3 may be a potential therapeutic agent for diabetes.