I prostanoid receptor-mediated inflammatory pathway promotes hepatic gluconeogenesis through activation of PKA and inhibition of AKT

  1. Ying Yu1,2,*
  1. 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, 200031, China
  2. 2Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China
  3. 3Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
  1. *Corresponding Author: Ying Yu, E-mail: yuying{at}sibs.ac.cn
  1. ^ Equal contribution

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin (ASA), improve glucose metabolism in diabetic subjects, although the underlying mechanisms remain unclear. In this study, we observed dysregulated expression of COX-2, prostacyclin biosynthesis, and the I prostanoid receptor (IP) in the livers 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 starving-induced hepatic gluconeogenesis, thus inhibiting the progression of diabetes, while hepatic overexpression of IP increased gluconeogenesis. IP deletion depressed cAMP-dependent CREB phosphorylation and elevated AKT phosphorylation by suppressing PI3Kγ/PKCζmediated TRB3 expression, which subsequently down-regulated the gluconeogenic genes for glucose-6-phosphatase (G6Pase) and phosphoenol pyruvate carboxykinase 1 (PEPCK1) in hepatocytes. We therefore, conclude that suppression of IP modulation of hepatic gluconeogenesis through the PKA/CREB and PI3Kγ/PKCζ/TRB3/AKT pathways contributes to the effects of NSAIDs in diabetes.

  • Received December 18, 2013.
  • Accepted April 2, 2014.

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This Article

  1. Diabetes