胃旁路术后GLP-1受体多态性对β细胞的影响及机制研究

Roux-en-Y gastric bypass affects human material and energy metabolism. After the surgery patients with type 2 diabetes mellitus (T2DM) obtained effective weight loss and blood sugar improvement. The increase of glucagon-like peptide-1 (GLP-1) contributes to the glycometabolism improvement. In our clinical work and previous research, we found that all patients had a higher GLP-1 level after surgery. However, not every patient performed significant blood sugar improvement. Single Nucleotide Polymorphisms (SNPs) of GLP-1 Receptor (GLP1R) gene affect the receptor function and in vivo responses on GLP-1. We speculate that SNPs of GLP1R play an important role on the outcomes of gastric bypass. We plan to study gastric bypass animal model and β cell in vitro. The effect of SNPs on postoperative insulin secretion level of β cell and glucose metabolism index will be evaluated, the role of GLP1R variants on signal channels are also be investigated. In this study, GLP1R polymorphisms and β cell secretion are used as the breakthrough points to explore the mechanism of β cell secretion improved after gastric bypass, it will provide a theoretical basis for the individualized surgical treatment for T2DM.

胃旁路术影响机体的物质代谢与能量代谢，可有效降低体重并改善血糖。术后胰高血糖素样肽-1（GLP-1）分泌增加是血糖改善的主要原因之一。临床工作及前期研究中我们发现胃旁路术后虽GLP-1水平均有升高，但并非所有2型糖尿病患者都能获得有效的血糖控制。GLP-1受体基因单核苷酸多态性影响受体功能及GLP-1的在体反应，提示该受体的单核苷酸多态性对胃旁路术疗效有影响。本研究以GLP-1受体多态性与β细胞分泌功能为切入点，以胃旁路术动物模型和β细胞为研究对象，在体观察GLP-1受体基因多态性对术后胰岛素分泌和糖代谢指标的影响，离体探索GLP-1受体多态性影响β细胞功能改善的具体机制，为2型糖尿病个体化手术治疗提供理论基础。

胃旁路术（RYGB）影响机体的物质代谢与能量代谢，可有效降低体重并改善血糖。术后胰高血糖素样肽-1（GLP-1）分泌增加被认为是血糖改善的主要原因之一。本项目前期提出GLP-1受体（GLP1R）的单核苷酸多态性（SNPs）可能是影响GLP-1诱导的β细胞分泌，限制RYGB临床疗效的重要原因。因此本项目首先建立了一种RYGB 2型糖尿病（T2DM）大鼠模型，并证实RYGB术后GLP-1显著升高，胰腺内存在451种差异蛋白，富集于核糖体、胰腺分泌、蛋白质消化/吸收等过程。其后利用在线数据库ensembl分析发现人体内rs10305420、rs3765467、rs6923761、rs2235868、rs1042044、rs367543060和rs10305492等7个GLP1R SNP位点可能影响GLP-1功能和RYGB手术疗效，利用离体大鼠胰岛β细胞系和GLP-1类似物/拮抗剂干预发现SNP rs3765467和rs10305492可影响胰岛β细胞功能和凋亡，且其功能发挥与GLP-1密切相关。最后，临床回顾性分析发现除BMI外，总体脂率、android区体脂率也可作为RYGB实施的重要评估指标。通过阐明SNPs多态性对β细胞分泌功能影响的具体机制，有助于今后基于SNPs基因分型的代谢手术个体化治疗的推进，对T2DM的防治具有特殊意义。