胃旁路手术调控SGLT3协同SGLT1介导消化道葡萄糖吸收在治疗2型糖尿病中的作用及其机制研究

Type 2 diabetes mellitus (T2DM), is a major economic and public health problem throughout the emerging developing countries and developed countries. Reports have confirmed that type 2 diabetes mellitus (T2DM) was completely greatly improved or cured after Roux-en-Y gastric bypass surgery, and the effect of improving the symptoms of diabetes was better than mere medication. Therefore, researching the mechanism of RYGB which controls the glucose level actively contribute to expand train of thought for T2DM treatment..We conduct this innovative work, focus on the sodium-coupled glucose co-transporter 3(SGLT3), which is a glucose sensor. By investigating difference of distribution and expression of SGLT3, the relationship will been verified among SGLT3, SGLT1, and glucose absorption in vivo. Meanwhile, the expression of sglt1, glucose transport capacity of intestinal segment, glucose intake of cell will be researched after SGLT3 silencing in vitro. We want to prove that SGLT3 is a important potential target for glucose absorption, and provide a new theoretical basis and.practical guidance for T2DM.

2型糖尿病(Type 2 Diabetes Mellitus，T2DM)是新兴发展中国家和发达国家面临的重大经济和公共健康问题。研究证实2型糖尿病患者接受胃旁路手术(Roux-en-Y Gastric Bypass，RYGB)后得到较大程度改善或完全治愈，且疗效优于单纯药物治疗，故积极研究RYGB调控机体血糖水平的机制有助于扩展临床治疗T2DM的思路。本课题围绕葡萄糖感受器SGLT3来设计，在体实验试图明确RYGB手术前后不同肠段的SGLT3分布、表达与SGLT1的表达及全消化道葡萄糖吸收量之间的关系；体外实验通过siRNA沉默SGLT3，拟明确其与SGLT1表达、小肠节段葡萄糖转运能力、小肠平滑肌细胞葡萄糖摄取量之间的关系，试图证实SGLT3是影响消化道葡萄糖吸收的重要靶点，为2型糖尿病的治疗提供新的理论基础和实践指导。

背景：肥胖及Ⅱ型糖尿病已成为严重危害世界人类健康的慢性代谢性疾病，采用代谢减重手术对治疗肥胖及糖尿病具有重大意义。SGLT3(钠一葡萄糖共转运蛋白3)作为葡萄糖感受器存在于消化道，刺激SGLT3可促进葡萄糖的吸收，而胃肠道葡萄糖吸收转运主要由SGLT1来完成，同时我们先前研究表明SG术后SGLT1水平降低进而葡萄糖吸收减少，这样的结果与RYGB术后小鼠肠道的SGLT1降低的结果一致。由此，我们假设胃肠道的SGLT3是SGLT1的上游靶点，袖状胃减容术（sleeve gastric SG）后SGLT3丰度的降低导致了SGLT1表达的下降，引起胃肠道葡萄糖吸收减少,从而减低胃肠道葡萄糖吸收量抵抗糖尿病和肥胖症。 .主要研究内容：分别测定SG组和假手术组小鼠每日体重和摄食量1个月，并在术后30天时进行口服葡萄糖耐量试验以评估葡萄糖吸收情况，同时用D-葡萄糖、D-葡萄糖+SGLT3激动剂（α-甲基葡萄糖）、D-葡萄糖+SGLT1抑制剂（根皮苷）进行全肠灌注，测定相应肠段SGLT3，SGLT1的变化情况。人小肠上皮细胞（HIEC）于无糖血清培养，SGLT3激动剂、SGLT1抑制剂分别刺激人后测定SGLT3、SGLT1的表达。用苏木精和伊红染色检测小鼠多个肠段绒毛的变化。采用RT-PCR,荧光免疫分析法检测SGLT3、SGLT1的表达。.重要结果及关键数据：与假手术组相比,约一个月左右，SG小鼠减轻了9.88％的体重；与假手术组相比，SG组术后1天食物摄取急剧下降90.94％，在约8天后恢复到一个较为稳定水平但没有达到假手术组水平。HE染色显示SG小鼠肠段的绒毛高度，隐窝深度和绒毛表面积在术后14天、30天降低。PCR显示在SG后2周和1个月时SGLT3、SGLT1的mRNA均下降；免疫荧光的蛋白质丰度分布表明SGLT3，SGLT1在SG后2周和1个月时下降。行SGLT3激动剂灌注可使小肠SGLT3、SGLT1的表达升高约三倍；行SGLT1抑制剂根皮苷灌注使小肠SGLT1、SGLT3 降低约5倍。HIEC加药刺激实验得到相同结果。.科学意义：SG可以使小鼠肠道的SGLT3，SGLT1表达降低，胃肠葡萄糖吸收减少；SGLT3作为葡萄糖的上位传感器，SGLT3的变化引起SGLT1的变化，提示SGLT3可以作为肥胖症及糖尿病治疗的潜在靶点。

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