胆汁酸代谢异常致胃肠胰岛轴功能失衡在GDM发病中的作用机制研究

妊娠期糖尿病（GDM）以餐后血糖超标为主，空腹血糖对GDM的诊断价值有限。餐后血糖除受胰岛素及胰高血糖素调控外，也受胃肠胰岛轴的动态调节。妊娠期特有的胃肠功能失调可能推动GDM发生。前期发现，GDM患者血清雌孕激素水平和结合型胆汁酸水平高于正常；GDM小鼠模型血清胆汁酸浓度高于对照，GLP-1响应值低于对照，胃排空速率高于对照；在其离体小肠中输入胆汁酸，肠系膜血管灌流液中可检测到GLP-1。我们提出“由于基因多态性对胆汁酸受体、胆汁酸转运体和激素代谢的影响，导致部分孕妇出现胆汁酸转运障碍，排入小肠的胆汁酸减少，进而GLP-1生成减少，胃肠胰岛轴功能失衡，使餐后血糖异常升高，超出人体对餐后血糖的控制能力，诱发GDM”的科学假说。本项目拟利用临床研究、动物试验和体外模型，系统研究妊娠期餐后血糖调节通路及其在GDM中扮演的角色，以全新角度诠释GDM的病生过程，为研究其发病机制提供新思路。

Gestational diabetes mellitus (GDM) is characterized by postprandial hyperglycemia, while fasting blood glucose shows limited value in its diagnosis. Postprandial blood glucose was not only regulated by insulin and glucagon, but also by gastrointestine-pancreas islet axis. Characteristic changes in gastrointestinal function during gestation may trigger the onset of GDM. We have observed abnormal levels of estrogen, progestogen and conjugated bile acids in GDM patients. GDM mice also displayed higher serum bile acid levels, lower GLP-1 responses and higher gastric emptying rates than the controls. Infusion of bile acids into the mouse intestines resulted in GLP-1 detection in the perfusate of mesenteric vessel. We hypothesize that “due to gene polymorphism on bile acid receptors, bile acid transporters and hormone metabolism, some pregnant women may display abnormal bile acid metabolism, causing reduced excretion of GLP-1 and imbalance of the gastrointestine-pancreas islet axis, which induces postprandial hyperglycemia that exceeded the control of the body, and results in GDM”. We plan to comprehensively investigate the above-mentioned pathway and its role in GDM using clinical studies, animal trials and in vitro models, in the hope of revealing the pathophysiology of GDM and providing a novel perspective for the study of its etiology.