胆胰液转流在手术治疗2型糖尿病作用中的机制研究

The mechanism underlying the therapeutic effect of Roux-en-Y Gastric bypass(RYGB) targeting Type 2 diabetes mellitus is still not clarified yet. The proposed “hormone hypothesis” itself can not fully address the hypoglycemic effect of RYGB. The duodenal-jejunal bypass(DJB) is commonly used in diabetes rodent model for the study of hypoglycemic effect post-operation, which includes billo-pancreatic diversion and duodenal-jejunal exclusion, resulting a stable and reliable hypoglycemic effect. Our pilot study showed that billo-pancreatic diversion alone can decrease both blood gulcose level and lipids level in short-term, but long-term effect was not satisfied. Duodenal-jejunal exclusion alone had no effect on blood gulcose/lipids levels. We therefore hypothesize that the therapeutic effect of billo-pancreatic diversion on diabetes mellitus may result from the decreases of sugar and fats absorption, reduced lipotoxicity and the changes of bile acid pathway. Herein, in the current proposal we will perform DJB,new billo-pancreatic diversion(NBPD) and duodenal-jejunal Exclusion(DJE) surgeries for GK rats, 1. The digestion and absorption of sugar and fats will be evaluated by 13C isotope breath test, the calorific value of fecal and the intestinal transporters detection; 2. Post-operation lipotoxicity will be monitored by measuring the apoptosis rate of βcell and AMPK expression level in liver; 3. Diabetes mellitus post-surgical bile acid pathway activation will be accessed by bile acid receptors expression and downstream signal components in liver and intestine tissues. Our goal of the proposed research is to elucidate the possible mechanism illustrating the therapeutic effect of billo-pancreatic diversion on diabetes mellitus, and further provide better strategies in the patients treatment.

胃旁路术治疗2型糖尿病的机制不明，以往用“激素假说” 解释，但存在缺陷。研究手术降糖机制常用糖尿病模型鼠行十二指肠空肠旁路术，该术式既转流胆胰液又旷置肠道，降糖效果稳定可靠。我们前期研究发现，单纯转流胆胰液能降糖、降脂但远期效果减弱，而单纯旷置肠道不能降糖、降脂。因此我们推测手术降糖机制与胆胰液转流导致糖类脂类吸收减少、高脂毒性减轻及胆汁酸通路变化有关。为此，本课题对糖尿病模型鼠行十二指肠空肠旁路术、单纯胆胰转流术和单纯肠道旷置术，1.通过同位素呼气实验、粪便热值和肠道转运蛋白等检测，对术后糖类脂类的消化、吸收功能变化进行相对独立的研究；2.通过检测大鼠术后β细胞凋亡率和肝脏AMPK表达水平，研究手术对高脂毒性的影响；3.通过检测肠道和肝脏胆汁酸受体及下游信号元件表达，探讨胆汁酸通路在手术降糖中的作用。希望经以上研究，明确胆胰液转流在手术降糖作用中的机制，为更好的治疗糖尿病提供理论依据。

胃旁路术治疗2型糖尿病的效果良好但机制不明，大量研究证实既转流胆胰液又旷置肠道的十二指肠空肠旁路术的降糖效果稳定可靠。我们前期的研究发现，单纯转流胆胰液能降糖、降脂但远期效果减弱，而单纯旷置肠道不能降糖、降脂。为了进一步证实手术降糖机制是否与胆胰液转流导致糖类脂类吸收减少、高脂毒性减轻及胆汁酸通路变化有关。我们设计了本课题，具体研究内容包括：对糖尿病模型鼠行十二指肠空肠旁路术、单纯胆胰转流术和单纯肠道旷置术，1.通过不同食物灌胃、同位素呼气实验、粪便热值和肠道转运蛋白等检测，对术后糖类脂类的消化、吸收功能变化进行相对独立的研究；2.通过检测大鼠术后β细胞凋亡率，研究手术对高脂毒性的影响；3.通过检测肠道和肝脏胆汁酸受体及下游信号元件表达，探讨胆汁酸通路在手术降糖中的作用。希望本课题的研究能为更好的治疗糖尿病提供理论和实验依据。