Betatrophin与妊娠期糖尿病的发生及产后转归的相关性研究

With the increasing prevalence of obesity and metabolic syndrome, the prevalence of gestational diabetes mellitus (GDM) has doubled over the last 6–8 years. A recent study claimed that betatrophin can boost β cell expansion in insulin resistant state. Pregnancy is a well-recognized physiological state of insulin resistance during which β cell proliferates to adapt to physiological needs and increased functional demands. Once, compensatory β cell expansion fails during pregnancy, gestational diabetes results. Our preliminary study showed that pregnant women had significantly higher betatrophin levels in comparison to unpregnant women. Furthermore, betatrophin levels were positively and significantly associated the β cell function. In the present study, we plan to enlarge the sample of GDM patients in cross-sectional study and compared the betatrophin levels among UP-NGR (unpregnant women with normal glucose regulation), P-NGR (pregnant women with NGR) and GDM and explore its relationships with β cell function. In the cohort study, we will investigate the incidence of GDM, impaired glucose regulation and diabetes 6-8 weeks after delivery. The associations between low betatrophin levels in first trimester and the incidence, prognosis of GDM will be evaluated prospectively. With all the efforts, we hope to provide new evidence regarding the association between betatrophin and GDM, new clues of the mechanism of GDM and new strategies of GDM prevention.

近年来妊娠期糖尿病（gestational diabetes mellitus, GDM）的患病率增加了近1倍。新近的研究发现，肝脏因子betatrophin在胰岛素抵抗的状态下可以促进胰岛β 细胞的增殖。我们的前期研究发现，betatrophin在GDM患者中的水平下降，且与胰岛β细胞功能呈正相关。本课题拟在前期横断面研究的基础上，比较正常糖代谢的未妊娠女性、正常糖代谢的妊娠女性以及GDM患者中betatrophin的水平。阐明betatrophin与胰岛素抵抗和胰岛细胞功能的相关性。采用队列研究了解GDM的发病率及产后6-8周糖调节异常及糖尿病的发病率，分析孕早期betatrophin水平与GDM的发生及其产后转归的相关性。通过本课题的研究，希望能为betatrophin与GDM的关系提供重要的流行病学证据，为探讨GDM的发病机制开拓新思路，为GDM的预防及预后提供新的策略。

妊娠期糖尿病（gestational diabetes mellitus, GDM）对母亲和子代的近远期代谢相关疾病都有重大影响。研究证实，对GDM的高危人群在孕早期进行饮食以及体育锻炼等生活方式的干预能显著降低GDM的发生率。因此，孕早期识别GDM的高危孕妇就尤为重要。但是，目前基于传统危险因素的风险模型预测GDM的效能差强人意，因此，亟待发现新的生物标志物已提高对GDM高危人群的识别能力。. 本研究通过横断面以及前瞻性队列研究评估孕早期betatrophin、FGF21以及氨基酸与GDM的相关性。横断面研究发现，与正常糖代谢的非妊娠女性相比，妊娠女性的betatrophin水平显著升高；但是在GDM患者和正常糖代谢妊娠女性间，betatrophin水平并无显著性差异。进一步的分析还发现，betatrophin水平与空腹胰岛素、HOMA胰岛素抵抗指数、HOMA-β细胞功能指数、总胆固醇、甘油三酯以及低密度脂蛋白胆固醇均相关；在校正血脂以后仍与HOMA-β细胞功能指数相关。队列研究的结果显示：与糖代谢正常的孕妇相比，GDM患者的betatrophin (ANGPTL8)、FGF21、丙氨酸、异亮氨酸以及酪氨酸水平在孕早期就已开始升高。在校正年龄、产次、糖尿病家族史、孕早期BMI以及孕早期空腹血糖后，betatrophin (ANGPTL8)、FGF21、丙氨酸、异亮氨酸以及酪氨酸仍与GDM的发病显著相关。进一步的分析还发现，ANGPTL8联合传统危险因素可将预测模型的受试者工作特征曲线 (receiver operating characteristic curve, ROC) 的曲线下面积 (area under curve, AUC)显著提高；孕早期异亮氨酸以及酪氨酸联合传统危险因素不仅可改善AUC，还可显著提高预测模型的净重新分类指数。. 本研究发现孕早期betatrophin、FGF21、异亮氨酸以及酪氨酸等生物标志物与GDM发病密切相关；整合传统危险因素及新的生物标志物，构建有效的GDM风险预测模型，可为GDM的早期预防提供新的流行病学依据，为防治策略提供新的思路。