不同节段的小肠旷置术治疗2型糖尿病的疗效及机制的对比研究

Jejunoileal bypass (JIB) was performed frequently as a bariatric surgical option for massive obesity and yielded significantly glycemic control with acceptable weight loss. Our previous studies found that side-to-side jejunoileal bypass plus proximal loop ligation (SSJIBL) induced better antidiabetic effects than end-to-side jejunoileal bypass (ESJIB) and SSJIBL is easier than ESJIB. Previous studies showed that jejunoileal bypass in different positions of small intestine all induced dramatic glucose-lowering effects. However, to date, very little systematic work has been done to study the comparison of curative effect between proximal intestinal bypass and mid intestinal bypass or distal small intestinal bypass on diabetes. Moreover, the mechanisms underlying this dramatic remission of T2DM following SSJIBL were not well understood. Furthermore, we assumed that changes of the gut microflora induced by physiological-anatomical changes might be a determinant of antidiabetic effects after SSJIBL. To investigate the above problems, we are going to develop four experimental intestinal procedures using the SSJIBL model, which was established by us. The four experimental intestinal procedures are duodenal-jejunal bypass (DJB), proximal small intestinal bypass (PSIB), mid small intestinal bypass (MSIB) and distal small intestinal bypass (DSIB), respectively. The antidiabetic effect of the four intestinal procedures and the changes of gut microflora of the T2DM rats will be then compared with each other to determine the contributions of the bypassed segment and the changed gut microflora to the improvement in glucose homeostasis after SSJIBL, which will provide experimental evidences for clinical application and modification of SSJIBL.

小肠旷置术（JIB）是最早应用于临床的减重手术之一，手术在取得满意的减重效果的同时也显著缓解了并发的2型糖尿病（T2DM）。我们研究发现，和传统的端侧吻合法小肠旷置术（ESJIB）相比，侧侧吻合加捆扎法小肠旷置术（SSJIBL）具有操作更简单、疗效更佳的优点。有研究报道，不同节段的JIB均能改善T2DM。然而，究竟旷置哪一节段的SSJIBL治疗T2DM的疗效最佳还不明确。此外，SSJIBL治疗T2DM的具体机制也需更深一步研究。我们推测，SSJIBL术后T2DM的改善可能与肠道微生物菌群变化密切相关。本研究将以我们前期建立的SSJIBL为手术模型，分别对T2DM大鼠(GK大鼠)施以十二指肠旷置术、近端小肠旷置术、中段小肠旷置术、远端小肠旷置术四种不同的手术，来系统探讨不同节段的SSJIBL治疗T2DM的疗效及机制，为临床上应用和改进SSJIBL治疗T2DM提供理论依据。

2型糖尿病（T2DM）是危害人类健康的重要疾病，和保守治疗相比，减重手术具有更佳的治疗效果。我们团队自主研发的侧侧吻合法小肠旷置术（SSJIBL）具有和经典减重手术同等的治疗效果，且具有手术操作更简单、可再恢复性的优点。然而，哪一节段的小肠在SSJIBL治疗T2DM的过程中起主要作用以及SSJIBL治疗T2DM的确切的机制目前还不十分明确。本项目通过实验比较十二指肠旷置术（DJB）、近端小肠旷置术（PSIB）、中段小肠旷置术（MSIB）、远端小肠旷置术（DSIB）治疗T2DM的疗效，发现PSIB、MSIB和DSIB这三种小肠旷置术降糖疗效明显优于十二指肠旷置术（DJB），此外，和MSIB及DSIB相比，PSIB降血糖疗效最佳且持久，而各手术后并发症及死亡率无明显差别。进一步对SSJIBL治疗T2DM机制进行探讨。我们发现：1. 血清Leptin水平与胰岛素水平及胰岛素敏感性正相关，提示Leptin降血糖的主要机制是提高胰腺β细胞功能；2. 免疫荧光提示DJB、PSIB、MSIB以及DSIB四种不同部位的小肠旷置术后均诱导了T2DM大鼠胰腺胰岛B细胞增生，胰岛分泌胰岛素明显增加，同时对比发现，PSIB组术后胰岛增殖抗原（PCNA）表达较DJB组明显增加，提示PSIB术对胰岛β细胞的促进作用更强；3. 二代测序对PSIB及Sham组肠道菌群测定结果显示：在门的水平，PSIB术后主要表现为变形杆菌门及厚壁菌门明显升高，而拟杆菌门明显降低。而在属的水平，拟杆菌属（Bacteroides）丰度和大鼠血糖、血脂、葡萄糖耐量以及胰岛素抵抗明显正相关，与胰岛β细胞增殖显著负相关。进一步分析拟杆菌属所含的菌种水平发现：埃氏拟杆菌（Bacteroides eggerthii）和粪拟杆菌（Bacteroides caccae）和胰岛素抵抗显著正相关，表明埃氏拟杆菌及粪拟杆菌丰度越高，胰岛素抵抗程度越强。本项目不仅明确了不同节段小肠旷置术治疗T2DM的疗效差别，同时也阐明了SSJIBL得降糖机制，即：SSJIBL术通过促进肠道分泌Leptin以及提高肠道拟杆菌种的丰度，进而提高了T2DM大鼠的胰岛β细胞功能。这为临床应用和改良SSJIBL治疗T2DM提供了依据，同时也为研究减重手术治疗T2DM的机制提供了新的思路。