转甲腺素蛋白TTR在妊娠期糖尿病发生发展中的作用及分子机制

Endocrine disturbance and abnormal placental function both affect fetal intrauterine environment in Gestational diabetes mellitus (GDM). Our previous study revealed that transthyretin (TTR) was abnormally elevated in serum and placenta of the third trimester of GDM, and serum TTR was positively correlated with fetal birth weight. In vitro, TTR and IGF-1 synergistically activated mTORC1 and promoted GLUT1 relocation to plasma membrane, suggesting that TTR was involved in the regulation of placental transport. In addition, serum TTR was positively correlated with retinol binding protein 4 (RBP4) in GDM, indicating that TTR may aggravate insulin resistance by inhibiting RBP4 metabolism. In order to explore the mechanism of TTR in GDM, this study is intended to: 1) improve the correlation of TTR with maternal/fetal metabolic markers in GDM through clinical samples; 2) reveal the mechanism of how TTR regulates placenta-specific amino acid and glucose transport; 3) clarify the regulation of TTR on RBP4 metabolism and explore the possibility of alleviating insulin resistance of GDM by antagonizing TTR. This study will help to elucidate the molecular mechanism of TTR in the development of GDM and to provide theoretical basis and potential therapeutic targets for improving the prognosis of GDM.

妊娠期糖尿病（GDM）内分泌代谢紊乱和胎盘功能异常共同影响胎儿宫内环境。课题组前期研究发现转甲状腺素蛋白（TTR）在GDM孕晚期血清、胎盘中异常升高，且血清TTR与胎儿出生体重呈正相关；体外实验提示TTR与IGF-1协同激活mTORC1，并促进胞膜上葡萄糖转运蛋白1（GLUT1）表达，提示TTR参与调控胎盘能量转运。此外，GDM血清TTR与视黄醇结合蛋白4（RBP4）呈正相关，提示TTR可能通过抑制RBP4代谢加剧GDM胰岛素抵抗。为探明TTR在GDM发病中具体机制，本研究拟：1）通过GDM临床数据进一步完善TTR与母胎代谢指标的相关性分析；2）从体外、体内水平揭示TTR调控胎盘对氨基酸、葡萄糖转运的具体机制；3）明确TTR对RBP4代谢的调控，探索下调TTR改善GDM胰岛素抵抗的可能。本研究有利于阐明TTR在GDM发生发展的分子机制，为改善GDM母婴预后提供理论依据和潜在治疗靶点。

妊娠期糖尿病（GDM）内分泌代谢紊乱和胎盘功能异常共同影响胎儿宫内环境，增加子代远期代谢性疾病发病风险。转甲状腺素蛋白(TTR) 在胎盘滋养细胞中表达，本研究发现GDM孕妇血清TTR含量明显高于糖耐量正常孕妇，且与空腹血糖、空腹胰岛素、HOMA-IR、新生儿体重呈正相关。在校正年龄、空腹血糖、空腹胰岛素后，血清TTR、孕妇BMI仍与新生儿体重成正相关。体外实验表明，TTR与IGF-1协同作用Bewo细胞，激活mTOR信号通路，促进氨基酸转运蛋白LAT1、LAT4蛋白表达升高，同时促进促使GLUT1、SNAT2、LAT1、LAT4由胞内向胞膜转移。动物实验结果显示，过表达TTR可增加GDM孕鼠体重，增大其胎鼠的体型，促进孕鼠胎盘mTOR信号通路活化，增加胎盘物质转运蛋白SNAT2、LAT1、LAT4表达。此外，我们采集了分娩巨大儿GDM孕妇、分娩适于胎龄儿GDM孕妇及分娩适于胎龄儿的正常孕妇胎盘组织及脐静脉血，采用非靶向代谢组学检测脐血中代谢物质，测定胎盘组织中的LAT1、LAT4表达和定位，结果显示亮氨酸、异亮氨酸和缬氨酸代谢通路及苯丙氨酸、酪氨酸和色氨酸代谢通路在三组间存在显著性差异，LAT1和LAT4在GDM巨大儿组中表达量最高，在对照组中表达量最低。本研究揭示TTR在GDM中的变化及其胎儿生长发育调控的作用机制，为GDM的病理机制和预防子代并发症提供理论依据。