Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China.
Front Endocrinol (Lausanne). 2021 Apr 27;12:663530. doi: 10.3389/fendo.2021.663530. eCollection 2021.
Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose . We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes ( and ) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.
细胞外 ADP 是 ATP 的衍生物，与细胞膜上的嘌呤能受体相互作用，调节细胞活动。这种信号通路在血糖调节中尚不清楚。我们通过腹腔注射研究了 ADP 在小鼠中的急性活性。在瘦鼠中，ADP 处理后血糖升高，丙酮酸耐量受损。肝葡萄糖生成增加，肝内糖异生基因（和）表达升高。在靶向代谢组学分析中，肝组织中 NADH、cAMP、AMP、GMP 和柠檬酸升高。在原代肝细胞中，ADP 激活了 cAMP/PKA/CREB 信号通路，该通路被 ADP 受体 P2Y13 的拮抗剂（2211）阻断。在循环中，ADP 升高了包括胰高血糖素和皮质酮在内的糖异生激素。血液中的胰岛素和甲状腺激素（T3 和 T4）没有改变。在饮食诱导肥胖（DIO）小鼠中，肝组织中 NADH 升高以匹配肝胰岛素抵抗。ADP 进一步加重胰岛素抵抗，加剧胰岛素耐受受损。这些数据表明，ADP 通过肝脏的直接和间接作用引起血糖升高。其中一种潜在途径涉及 P2Y13/cAMP/PKA/CREB 信号通路在肝细胞中的激活，间接途径可能涉及诱导糖异生激素。NADH 是 DIO 小鼠和瘦鼠肝脏中糖异生的信号。
