Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China.
World J Gastroenterol. 2022 Aug 21;28(31):4338-4350. doi: 10.3748/wjg.v28.i31.4338.
The mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids (BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB.
To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1.
Twenty diabetic rats were randomly allocated to the sham ( = 10) and DJB ( = 10) groups. Body weight, food intake, fasting blood glucose (FBG), serum and intraduodenal total BA (TBA) levels were measured accordingly. Oral glucose tolerance test (OGTT) and intraperitoneal pyruvate tolerance test (ipPTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor (FXR), small heterodimer partner (SHP), and Takeda G-protein-coupled receptor 5 (TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK (p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes.
The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ipPTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated mRNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the mRNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells.
DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.
十二指肠空肠旁路（DJB）后糖尿病缓解的机制仍不清楚。在 DJB 手术中，十二指肠被排除在外。然而，十二指肠已成为葡萄糖稳态的重要调节剂，升高的十二指肠 SIRT1 可导致肝胰岛素敏感性改善。DJB 后，十二指肠中的胆汁酸（BA）不能与摄入的食物混合和稀释。BA 受体的激活可促进许多组织中 SIRT1 的表达。我们假设 BA 介导的 SIRT1 上调可能有助于 DJB 后的糖尿病控制。
研究 DJB 对十二指肠 SIRT1 表达的手术影响，并揭示 BA 和 SIRT1 之间的潜在联系。
将 20 只糖尿病大鼠随机分为假手术（ = 10）和 DJB（ = 10）组。相应地测量体重、食物摄入量、空腹血糖（FBG）、血清和十二指肠总 BA（TBA）水平。口服葡萄糖耐量试验（OGTT）和腹腔内丙酮酸耐量试验（ipPTT）用于评估手术对全身葡萄糖处置和肝糖异生的影响。术后 8 周评估十二指肠黏膜中 BA 信号通路的关键基因，包括法尼醇 X 受体（FXR）、小异二聚体伴侣（SHP）和 Takeda G 蛋白偶联受体 5（TGR5），通过实时定量聚合酶链反应。通过 Western 印迹评估十二指肠 SIRT1、AMPK 和磷酸化 AMPK（p-AMPK）水平。用 GW4064 和 INT-777 处理大鼠小肠上皮 IEC-6 细胞，以验证 BA 对肠细胞中 SIRT1 表达的影响。
DJB 组在所有术后时间点的体重和食物摄入量均与假手术组相当。FBG 水平以及 OGTT 和 ipPTT 的曲线下面积在 DJB 组明显降低。DJB 组术后 2 周和 8 周时空腹和餐后血清 TBA 水平均高于假手术组。术后 8 周时，DJB 组十二指肠降段和水平段 TBA 浓度升高，FXR 和 SHP mRNA 表达上调，SIRT1 和 p-AMPK 蛋白表达升高。GW4064 和 INT-777 激活 FXR 和 TGR5 受体可增加 IEC-6 细胞中 SIRT1 的 mRNA 和蛋白表达，并促进 AMPK 的磷酸化。
DJB 可升高十二指肠 BA 水平并激活十二指肠 BA 信号通路，这可能上调十二指肠 SIRT1，进一步有助于 DJB 后葡萄糖稳态的改善。
