Abstract
Excessive hepatic glucose production (HGP) is a major cause of fasting hyperglycemia in diabetes and antihyperglycemic therapy takes center stage. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid(Aspirin), reduce hyperglycemia caused by unrestrained gluconeogenesis in diabetes, but its mechanism is incompletely understood. Here, we reported that aspirin lowers fasting blood glucose and hepatic gluconeogenesis, corresponds with lower thromboxane A2 (TXA2) levels, and the hypoglycemic effect of aspirin could be rescued by TP agonist treatment. Upon fasting and diabetes stress, the cyclooxygenase (COX)/TXA2/thromboxane A2 receptor (TP) axis was increased in the livers. TP deficiency suppressed starvation-induced hepatic glucose output, thus inhibiting the progression of diabetes, whereas TP activation promoted gluconeogenesis. Aspirin restrains glucagon signaling and gluconeogenic gene expression (phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6Pase)) through TXA2/TP axis. TP mediates hepatic gluconeogenesis by activating PLC/IP3/IP3R signaling, which subsequently enhanced CREB phosphorylation via facilitating CRTC2 nuclear translocation. Thus, our findings demonstrate that TXA2/TP plays a crucial role in aspirin's inhibition of hepatic glucose metabolism, and TP may represent a therapeutic target for diabetes.
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