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.
- © 2014 by the American Diabetes Association.
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