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 O1), 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.
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Research Article|
March 17 2014
GdCl3 reduces hyperglycaemia through Akt/FoxO1-induced suppression of hepatic gluconeogenesis in Type 2 diabetic mice
Qian Wang;
Qian Wang
*Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China
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Ning Wang;
Ning Wang
*Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China
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Mei Dong;
Mei Dong
*Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China
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Fang Chen;
Fang Chen
*Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China
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Zhong Li;
Zhong Li
*Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China
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Yuanyuan Chen
*Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China
Correspondence: Dr Yuanyuan Chen (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 21 2013
Revision Received:
January 13 2014
Accepted:
January 21 2014
Accepted Manuscript online:
January 21 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (2): 91–100.
Article history
Received:
October 21 2013
Revision Received:
January 13 2014
Accepted:
January 21 2014
Accepted Manuscript online:
January 21 2014
Citation
Qian Wang, Ning Wang, Mei Dong, Fang Chen, Zhong Li, Yuanyuan Chen; GdCl3 reduces hyperglycaemia through Akt/FoxO1-induced suppression of hepatic gluconeogenesis in Type 2 diabetic mice. Clin Sci (Lond) 1 July 2014; 127 (2): 91–100. doi: https://doi.org/10.1042/CS20130670
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