基于GLP-1的“肠促胰素效应”研究口服枸杞多糖抗T2DM的作用机制

Type 2 diabetes mellitus (T2DM) has been an increasingly serious health problem throughout the world. Incretin effect of GLP-1 was closed relevant to T2DM. Lycium Barbarum polysaccharide (LBP), a kind of main active ingredient extracted from Lycium Barbarum, has been demonstrated its anti-T2DM efficacy in many researches. In our previous study, we found that LBP reduces glucose uptake via sodium/glucose cotransporter 1 (SGLT-1). It has been proved that SGLT-1 triggers depolarization of cell membrane and secretion of GLP-1 during the transportation of glucose and sodium. Combined with our study and extensive references, it is hypothesized that LBP participates incretin effect of GLP-1. Therefore, this project will observe the effect of LBP on serum GLP-1 and its in situ expression in intestinal tissue of KKAy mice (T2DM model animal) to clear the relationship between GLP-1 secretion and serum DPP-4, intestinal α - glucosidase as well as GCG mRNA in intestinal tissue. Then mechanism of LBP on GLP-1 secretion will be explored through Wnt, cAMP/Epac and SGLT-1 path using STC-1 cell strain. This project studies systematically anti-T2DM mechanism of LBP from GCG expression, GLP-1 secretion and its activity maintaining based on incretin effect of GLP-1, in order to provide a theoretical basis for the application of LBP on T2DM treatment.

糖尿病已成为严重的全球健康问题。研究证实GLP-1的“肠促胰素效应”与2型糖尿病（T2DM）密切相关。枸杞多糖（LBP）是枸杞的主体成分，其降糖作用已在动物和人群实验中证实。前期研究我们发现LBP能够调节钠-葡萄糖协同转运体（SGLT-1）抑制葡萄糖吸收。有研究表明SGLT-1在转运葡萄糖和Na+过程中会触发细胞膜去极化，刺激GLP-1分泌。结合实践和大量文献证实，我们猜测LBP可能参与了GLP-1的肠促胰素效应。因此本研究拟先观察LBP对T2DM模型KKAy小鼠血清GLP-1水平和肠原位表达的作用，研究血清DPP-4、肠α-葡萄糖苷酶和肠组织GCG基因与GLP-1分泌的关系；再利用STC-1细胞研究LBP经Wnt、cAMP/Epac通路和SGLT-1途径对GLP-1分泌影响的分子机制。从GCG表达、GLP-1分泌和活性维持三方面，系统地研究LBP对GLP-1肠促胰素效应影响的作用机制。

糖尿病已成为严重的全球健康问题。研究证实GLP-1的“肠促胰素效应”与2型糖尿病（T2DM）密切相关。枸杞多糖（LBP）是枸杞的主体成分，其降糖作用已在动物和人群实验中证实。前期研究我们发现LBP能够调节钠-葡萄糖协同转运体（SGLT-1）抑制葡萄糖吸收。有研究表明SGLT-1在转运葡萄糖和Na+过程中会触发细胞膜去极化，刺激GLP-1分泌。结合实践和大量文献证实，我们猜测LBP可能参与了GLP-1的肠促胰素效应。.本研究从GCG表达、GLP-1分泌和活性维持三方面入手，观察了LBP对T2DM模型KKAy小鼠血清GLP-1水平和肠原位表达的作用，明确了血清DPP-4、肠α-葡萄糖苷酶和肠组织GCG基因与GLP-1分泌的关系；然后利用STC-1细胞研究了LBP经Wnt、cAMP/Epac通路和SGLT-1途径对GLP-1分泌影响的分子机制，系统地研究了LBP对GLP-1肠促胰素效应影响的作用机制。研究发现LBP能够通过激活Wnt/β-catenin信号通路、cAMP/Epac途径，激活下游靶基因GCG基因；并通过抑制SGLT1的蛋白的表达，调节细胞中Ca2+浓度，影响了GLP-1的表达；但是LBP不能抑制DPP-4活性进而避免GLP-1的降解。 .研究提示，我们或许可以利用LBP刺激GLP-1分泌的作用，将其与DPP-4抑制剂联合应用。一方面通过促进GLP-1分泌来促进糖尿病患者体内胰岛素分泌，另一方面通过抑制α-葡萄糖苷酶活性达到延迟碳水化合物吸收，延缓血糖升高的效果。