I Prostanoid Receptor–Mediated Inflammatory Pathway Promotes Hepatic Gluconeogenesis Through Activation of PKA and Inhibition of AKT (original) (raw)
Metabolism| August 16 2014
1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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2Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA
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1Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
3Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China
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S.Y. and Q.Z. contributed equally to this work.
Diabetes 2014;63(9):2911–2923
Citation
Shuai Yan, Qianqian Zhang, Xiaojing Zhong, Juan Tang, Yuanyang Wang, Junjie Yu, Yi Zhou, Jian Zhang, Feifan Guo, Yi Liu, Garret A. FitzGerald, Ying Yu; I Prostanoid Receptor–Mediated Inflammatory Pathway Promotes Hepatic Gluconeogenesis Through Activation of PKA and Inhibition of AKT. _Diabetes 1 September 2014; 63 (9): 2911–2923. https://doi.org/10.2337/db13-1893
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Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA), improve glucose metabolism in diabetic subjects, although the underlying mechanisms remain unclear. In this study, we observed dysregulated expression of cyclooxygenase-2, prostacyclin biosynthesis, and the I prostanoid receptor (IP) in the liver’s response to diabetic stresses. High doses of ASA reduced hepatic prostaglandin generation and suppressed hepatic gluconeogenesis in mice during fasting, and the hypoglycemic effect of ASA could be restored by IP agonist treatment. IP deficiency inhibited starvation-induced hepatic gluconeogenesis, thus inhibiting the progression of diabetes, whereas hepatic overexpression of IP increased gluconeogenesis. IP deletion depressed cAMP-dependent CREB phosphorylation and elevated AKT phosphorylation by suppressing PI3K-γ/PKC-ζ–mediated TRB3 expression, which subsequently downregulated the gluconeogenic genes for glucose-6-phosphatase (G6Pase) and phosphoenol pyruvate carboxykinase 1 in hepatocytes. We therefore conclude that suppression of IP modulation of hepatic gluconeogenesis through the PKA/CREB and PI3K-γ/PKC-ζ/TRB3/AKT pathways contributes to the effects of NSAIDs in diabetes.
© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
2014
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