AMPK在十二指肠空肠旁路术后脂质感受调控肝葡萄糖输出中的作用及机制研究

Duodenal-jejunal bypass could rapidly and sustainably improve the glucose metabolism of diabetic rats, while the intrinsic mechanisms are still elusive. The early amelioration of T2DM after DJB is mainly induced by reduced hepatic glucose production, which is the improvement of the hepatic insulin sensitivity. The duodenum can regulate hepatic glucose production through gut-brain-liver axis by sensing lipid or drugs in the duodenal lumen, which can activate/inhibit AMPK signaling. The duodenal AMPK activity is significantly inhibited in the condition of obese or diabetes, while AMPK activity is significantly raised after DJB. Based on the above research, we speculate that: DJB bypassed the duodenum in which the AMPK activity was inhibited, and restored the activity of AMPK, and then restored the physiologic state of gut-brain-liver axis in the regulation of hepatic glucose product. In the present study, we would investigate the roles and mechanisms of duodenal AMPK in the regulation of hepatic glucose product induced by duodenal lipid sensing after DJB in the diabetic rat model induced by high lipid and low dose of STZ.

十二指肠空肠旁路术（DJB）可以迅速而持久的改善糖尿病大鼠的糖代谢，但具体机制尚不明确。术后早期T2DM的改善主要源于肝葡萄糖输出的减少。十二指肠可以通过感受其内脂质及某些药物浓度的变化，通过激活/抑制AMPK信号通路并通过肠-脑-肝轴而调节肝葡萄糖输出。肥胖及糖尿病状态下十二指肠AMPK活性明显下降，前期研究发现DJB术后十二指肠AMPK活性明显升高。因此我们推测：DJB旷置了AMPK受抑制的十二指肠，解除了营养物质对AMPK的抑制，恢复了生理状态下肠-脑-肝轴对HGP的调节作用，从而改善了糖代谢。本实验以高脂饲料联合低剂量STZ诱导的糖尿病大鼠为模型，并建立DJB手术及假手术模型，通过十二指肠置管-灌注及基础胰岛素-正葡萄糖钳夹实验等研究十二指肠AMPK在DJB术后十二指肠脂质感受调控肝葡萄糖输出中的作用及机制，进一步明确旷置的十二指肠在DJB术后糖代谢改善中的作用及机制。

胃旁路术可以迅速而持久的改善糖尿病大鼠的糖代谢，但具体机制尚不明确。术后早期T2DM的改善主要源于肝葡萄糖输出的减少。十二指肠可以通过感受其内脂质及某些药物浓度的变化，通过激活/抑制AMPK信号通路并通过肠-脑-肝轴而调节肝葡萄糖输出。本课题组结合前期研究，建立糖尿病大鼠模型，并建立了十二指肠-空肠旁路术及袖状胃切除手术模型，通过十二指肠内灌注不同药物，结合OGTT、ITT、基础胰岛素正葡萄糖钳夹实验等评估胰岛素敏感性的改变，检测十二指肠粘膜内AMPK、p-AMPK、GLP-1R及PKA等信号通路的变化，证实了十二指肠内AMPK信号通路参与调节胃旁路术后糖耐量的改善。本研究进一步阐明了胃旁路术治疗2型糖尿病的机制，揭示了十二指肠AMPK信号通路在胃旁路术后糖耐量改善中的左右，为糖尿病的治疗提供了新思路。