Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine (ADO) to inosine and regulates ADO concentration. ADA ubiquitously expresses in various tissues to mediate ADO-receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus. Here, we show that elevated plasma ADA activity is a compensated response to high level of ADO in type 2 diabetes mellitus and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA, can reduce ADO levels and decrease hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in and high-fat streptozotocin diabetic mice. Mechanistically, ADA catabolizes ADO and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.

中文翻译：

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腺苷脱氨酶在调节小鼠糖异生中的关键作用


腺苷脱氨酶 (ADA) 催化腺苷 (ADO) 不可逆脱氨基为肌苷并调节 ADO 浓度。 ADA 在多种组织中广泛表达，介导 ADO 受体信号传导。血浆 ADA 活性的显着增加已被证明与 2 型糖尿病的发病机制有关。在这里，我们发现血浆 ADA 活性升高是 2 型糖尿病患者对高水平 ADO 的补偿反应，并且在葡萄糖稳态调节中发挥重要作用。补充更多 ADA，而不是抑制 ADA，可以降低 ADO 水平并减少肝脏糖异生。 ADA 可恢复正常血糖状态并恢复高脂链脲佐菌素糖尿病小鼠的功能性胰岛。从机制上讲，ADA 分解代谢 ADO 并增加 Akt 和 FoxO1 磷酸化，不依赖于胰岛素作用。与胰岛素相比，ADA 降低血糖的速度较慢且持续时间较长，从而延缓或阻止胰岛素源性低血糖休克的发生。最后，ADA 抑制禁食小鼠和胰岛素缺乏的糖尿病小鼠的糖异生，表明 ADA 调节糖异生是一种普遍的生物学机制。总体而言，这些结果表明 ADA 有望成为糖尿病的新治疗靶点。