胆汁酸信号在改良空回肠旁路术后调节肝肠糖异生的机制研究

Jejunoileal bypass (JIB) was performed frequently as a bariatric surgical option for massive obesity and had become obsolete due to the complications of the procedure. Our previous studies found that side-to-side jejunoileal bypass plus proximal loop ligation (SSJIBL) induced dramatic weight-losing and glucose-lowering effects and SSJIBL had the advantages of simple operation and low rate of complications. However, the mechanisms underlying this dramatic remission of T2DM following SSJIBL is not well understood. Recent studies show that the bile acids (BA) signaling is closely related to the remission of T2DM after bariatric surgery. BA signaling improved the glucose metabolism through regulating the hepatic and intestinal gluconeogenesis. However, the mechanisms that explain it remain unclear. Our previous study revealed that the enhanced primary BA systhesis was the main cause of the elevated serum BA level following SSJIBL and these alterations aim to enhance incretin release and insulin sensitivity, which ultimately has beneficial effects on glucose homeostasis. So we hypothesize that the changes of the BA signaling improved the glucose metabolism by regulating the hepatic and intestinal gluconeogenesis. To address this issue, we plan to develop two different experimental surgery models using T2DM and obese rats. The two procedures were SSJIBL and bile diversion. The aim of this study was to explore the mechanisms of the bile acids signaling in regulating hepatic and intestinal gluconeogenesis after SSJIBL and provide the theoretical foundation for the clinical application of the SSJIBL to treat non-obese T2DM.

空回肠旁路术（JIB）是临床应用的减重手术之一，但因并发症而渐被淘汰。申请者自主研发的侧侧吻合加近端肠袢捆扎法JIB（SSJIBL）具有明显的减重和降糖疗效，且并发症少、操作简单。然而SSJIBL治疗T2DM的机制尚不明确。研究发现胆汁酸（bile acids, BA）信号和减重手术后T2DM的缓解密切相关。BA信号通过调节肝肠糖异生来改善葡萄糖代谢，但其机制尚不明确。申请者前期研究发现SSJIBL术后初级BA合成的增加是SSJIBL术后血清BA升高的主要原因，且升高的BA水平和糖耐量改善密切相关。我们推测：BA信号在SSJIBL术后可能通过调节肝肠糖异生来改善葡萄糖代谢。为了证实以上推测，本项目以T2DM及肥胖大鼠为研究对象，以SSJIBL和胆汁转流为手术模型展开研究，来系统探讨BA信号在SSJIBL术后调节肝肠糖异生的作用机制，为临床应用SSJIBL治疗非肥胖型T2DM提供理论基础。

侧侧吻合法小肠旷置术（SSJIBL）具有良好的改善血糖代谢的疗效，并且具有手术操作简便、可复性及并发症少等优点。然而SSJIBL治疗糖尿病的具体机制尚不明确。研究发现胆汁酸（bile acids, BA）信号和减重手术后T2DM的缓解密切相关。BA信号通过调节肝肠糖异生来改善葡萄糖代谢，但其机制尚不明确。本项目通过实验研究发现：..1.通过将SSJIBL与胆汁回肠转流术（BID）进行对比，血清总胆汁检测发现SSJIBL和BID术后总胆汁酸明显升高，进一步分析，血清和粪便胆汁酸靶向代谢组发现牛磺石胆酸和牛磺脱氧胆酸与餐后血糖成正相关，提示牛磺石胆酸和牛磺脱氧胆酸参与血糖代谢主要是调控餐后血糖；2.SSJIBL术后肝脏胆汁酸相关酶谱分析发现胆汁合成酶明显升高，尤其是cyp27a1表达量明显升高，提示胆汁酸水平升高主要是通过合成增加；3.SSJIBL术后检测肝脏糖异生关键酶基因表达水平，发现葡萄糖-6-磷酸酶-1（G6PC-1）和磷酸烯醇丙酮酸羧化酶-1（PERCK-1）相对表达量假手术组明显下降，提示SSJIBL可以调节肝脏糖异生来改善葡萄糖代谢。本项目明确了SSJIBL具有BID降血糖的同等效应，同时阐明了SSJIBL改善血糖代谢的机制，即：SSJIBL术通过增加胆汁酸的合成升高胆汁酸水平，进而调控肝脏糖异生。这为临床应用SSJIBL治疗非肥胖型T2DM提供理论依据，同时也为研究代谢手术治疗T2DM的机制提供了新的思路。