I prostanoid receptor-mediated inflammatory pathway promotes hepatic gluconeogenesis through activation of PKA and inhibition of AKT.
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.
Key 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.
Shuai
S
Yan
Key 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.
Qianqian
Q
Zhang
Key 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.
Xiaojing
X
Zhong
Key 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.
Juan
J
Tang
Key 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.
Yuanyang
Y
Wang
Key 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.
Junjie
J
Yu
Key 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.
Yi
Y
Zhou
Key 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.
Jian
J
Zhang
Key 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.
Feifan
F
Guo
Key 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.
Yi
Y
Liu
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA.
Garret A
GA
FitzGerald
Key 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 Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China yuying@sibs.ac.cn.
Ying
Y
Yu
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D059305:Diet, High-Fat; D011464:Epoprostenol / Q000502:physiology; D005215:Fasting; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000502:physiology*
D018797:Cell Cycle Proteins; C491910:Ptgir protein, mouse; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C474830:TRB3 protein, mouse; D011464:Epoprostenol; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D005952:Glucose-6-Phosphatase; D001241:Aspirin