袖状胃切除术后小肠和下丘脑营养感受对肝脏葡萄糖输出的调节

Sleeve gastrectomy surgery induces rapid and durable remission of diabetes. However, the exact mechanisms remain ambiguous. Our previous studies have confirmed that the rapid improvement of diabetes after sleeve gastrectomy is tightly associated with reduced hepatic glucose production, which is physiologically regulated by nutrient sensing in small intestine and hypothalamus through activating the "gut-brain-liver" axis and " brain-liver". The development of diabetes is associated with the impaired nutrient sensing in small intestine and hypothalamus. Based on the above research, we speculate that the impaired nutrient sensing in small intestine and hypothalamus is repaired after sleeve gastrectomy. The repaired nutrient sensing regulates hepatic glucose production and alleviates diabetes. The present study is initiated to confirm the repairment and regulation of hepatic glucose production by nutrient sensing in the proximal intestine, distal intestine and hypothalamus, using basal insulin-euglycemic clamp test, gut infusion and lateral ventricle infusion techniques on STZ-induced type 2 diabetes Wistar rats after sleeve gastrectomy. This study aims to discuss the regulation of hepatic glucose production by small intestine and hypothalamus nutrient sensing after sleeve gastrectomy, and to further reveal the mechanisms of diabetes remission after sleeve gastrectomy.

袖状胃切除术能迅速、持久地缓解糖尿病，但其机制尚不明确。本课题组前期研究发现，袖状胃切除术后糖尿病的迅速改善与肝脏葡萄糖输出减少密切相关，而小肠和下丘脑通过其营养感受机制分别激活肠-脑-肝轴和脑-肝轴对肝脏葡萄糖输出进行调节，小肠和下丘脑的营养感受机制受损与糖尿病形成有关。因此，本课题组推测：袖状胃切除术后，小肠和下丘脑的营养感受机制得以修复，通过激活肠-脑-肝轴和脑-肝轴对肝脏葡萄糖输出进行调节，进而改善糖代谢。本课题组拟以高脂喂养联合STZ诱导的糖尿病Wistar大鼠为动物模型，建立袖状胃切除术手术模型，通过小肠灌注、侧脑室灌注、基础胰岛素-正葡萄糖钳夹等技术研究袖状胃切除术后近端小肠、远端小肠和下丘脑的营养感受对肝脏葡萄糖输出的调节。本研究旨在探讨小肠和下丘脑营养感受机制对肝脏葡萄糖输出中的调节作用，进一步揭示袖状胃切除术缓解糖尿病的机制。

糖尿病是危害人类健康的主要疾病之一，其发病率逐年上升。临床研究证实，袖状胃切除术（SG）可显著缓解糖尿病，但其作用机制尚不清楚。本课题组前期研究发现，SG术后糖尿病的迅速改善与肝脏葡萄糖输出减少密切相关，而小肠和下丘脑通过其营养感受机制分别激活肠-脑-肝轴和脑-肝轴对肝脏葡萄糖输出进行调节，小肠和下丘脑的营养感受机制受损与糖尿病形成有关。本课题组推测：SG改善了小肠和下丘脑中受损的营养感受机制，恢复了对肝脏葡萄糖输出的正常调控，进而改善了糖代谢。本课题组拟以高脂喂养联合STZ诱导的糖尿病大鼠为动物模型，建立SG手术模型，研究SG术后近端小肠、远端小肠和下丘脑的营养感受对肝脏葡萄糖输出的调节。我们取得了以下几个方面结果：（一）SG能有效上调肝胰岛素信号通路中关键蛋白的表达及肠道糖异生的关键调控酶，并下调肝糖原异生的关键调控酶的表达。此研究有助于揭示肝胰岛素信号通路和肠道糖异生在改善代谢手术后胰岛素抵抗中的潜在作用。（二）SG上调了LCN-2的表达，下丘脑神经元细胞膜上LCN2-MC4R复合体及GLUT2同时也升高，提示SG可能通过LCN-2改善下丘脑对葡萄糖的感受功能，进一步调节糖代谢稳态。我们的研究可能为代谢手术治疗糖尿病提供新的理论依据及治疗靶点。