Blood glucose is of great importance to development and metabolic homeostasis in fetuses. Stimulation of harmful factors during gestation induces pathoglycemia. Angiotensin II type 1 receptor autoantibody (AT1-AA), a newly discovered gestational harmful factor, has been shown to induce intrauterine growth restriction in fetuses and glucose disorders in adults. However, whether and how AT1-AA influences the blood glucose level of fetuses during gestation is not yet clear. The purpose of the current study was to observe the fetal blood glucose level of AT1-AA-positive pregnant rats during late pregnancy and to determine the roles that hepatic glucose transporters play in this process. We established AT1-AA-positive pregnant rats by injecting AT1-AA into the caudal veins of rats in the 2nd trimester of gestation. Although the fetal blood glucose level in the 3rd trimester of gestation decreased, hepatic glucose uptake increased detected. Through separating membrane and cytosolic proteins, we demonstrated that both the expression and membrane transport ratio of glucose transporter 1 (GLUT1), which is responsible for glucose transport in fetal hepatocytes, were upregulated, accompanied by increased expression of N-glycosyltransferase STT3A, which contributes to the N-glycosylation of GLUT1. In vitro, we identified that AT1-AA increased glucose uptake, the expression and membrane transport ratio of GLUT1 and the expression of STT3A in HepG2 cell lines via separating membrane and cytosolic proteins and immunofluorescence, resulting in the decreased glucose content in the medium. The GLUT1 inhibitor WZB117 reversed the decreases in glucose content in the medium, the increases in glucose uptake, the increases in the expression and membrane transport ratio of GLUT1 caused by AT1-AA. The N-glycosyltransferase inhibitor NGI as well as si-STT3A reversed the AT1-AA-induced upregulation of the STT3A-GLUT1-glucose uptake effect. This study demonstrates that AT1-AA lowers the blood glucose level of fetuses via the STT3A-GLUT1-glucose uptake axis in liver.

血糖对胎儿的发育和代谢稳态非常重要。妊娠期间有害因素的刺激会诱发病理性血糖。血管紧张素 II 1 型受体自身抗体 (AT1-AA) 是一种新发现的妊娠有害因子，已被证明可诱导胎儿宫内生长受限和成人葡萄糖障碍。然而，AT1-AA是否以及如何影响妊娠期间胎儿的血糖水平尚不清楚。本研究的目的是观察妊娠晚期 AT1-AA 阳性妊娠大鼠的胎儿血糖水平，并确定肝葡萄糖转运蛋白在此过程中的作用。我们通过在妊娠第 2 个月向大鼠尾静脉注射 AT1-AA 来建立 AT1-AA 阳性妊娠大鼠。虽然在妊娠第 3 个月胎儿血糖水平下降，但检测到肝葡萄糖摄取增加。通过分离膜蛋白和胞质蛋白，我们证明了负责胎儿肝细胞葡萄糖转运的葡萄糖转运蛋白 1 (GLUT1) 的表达和膜转运比率均被上调，伴随着 N-糖基转移酶 STT3A 的表达增加，这有助于GLUT1 的 N-糖基化。在体外，我们通过分离膜和细胞溶质蛋白以及免疫荧光发现 AT1-AA 增加葡萄糖摄取、GLUT1 的表达和膜转运比率以及 STT3A 在 HepG2 细胞系中的表达，导致培养基中的葡萄糖含量降低。GLUT1抑制剂WZB117逆转了AT1-AA引起的培养基中葡萄糖含量的降低、葡萄糖摄取的增加、GLUT1的表达和膜转运比率的增加。N-糖基转移酶抑制剂 NGI 以及 si-STT3A 逆转了 AT1-AA 诱导的 STT3A-GLUT1-葡萄糖摄取作用的上调。该研究表明，AT1-AA 通过肝脏中的 STT3A-GLUT1-葡萄糖摄取轴降低胎儿的血糖水平。