School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona 85719, USA.
Endocrinology. 2022 Jun 1;163(6). doi: 10.1210/endocr/bqac053.
Placental insufficiency (PI) lowers fetal oxygen and glucose concentrations, which disrupts glucose-insulin homeostasis and promotes fetal growth restriction (FGR). To date, prenatal treatments for FGR have not attempted to correct the oxygen and glucose supply simultaneously. Therefore, we investigated whether a 5-day correction of oxygen and glucose concentrations in PI-FGR fetuses would normalize insulin secretion and glucose metabolism. Experiments were performed in near-term FGR fetal sheep with maternal hyperthermia-induced PI. Fetal arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction and glucose was infused into FGR fetuses (FGR-OG). FGR-OG fetuses were compared with maternal air insufflated, saline-infused fetuses (FGR-AS) and control fetuses. Prior to treatment, FGR fetuses were hypoxemic and hypoglycemic and had reduced glucose-stimulated insulin secretion (GSIS). During treatment, oxygen, glucose, and insulin concentrations increased, and norepinephrine concentrations decreased in FGR-OG fetuses, whereas FGR-AS fetuses were unaffected. On treatment day 4, glucose fluxes were measured with euglycemic and hyperinsulinemic-euglycemic clamps. During both clamps, rates of glucose utilization and production were greater in FGR-AS than FGR-OG fetuses, while glucose fluxes in FGR-OG fetuses were not different than control rates. After 5 days of treatment, GSIS increased in FGR-OG fetuses to control levels and their ex vivo islet GSIS was greater than FGR-AS islets. Despite normalization in fetal characteristics, GSIS, and glucose fluxes, FGR-OG and FGR-AS fetuses weighed less than controls. These findings show that sustained, simultaneous correction of oxygen and glucose normalized GSIS and whole-body glucose fluxes in PI-FGR fetuses after the onset of FGR.
胎盘功能不全（PI）降低胎儿的氧和葡萄糖浓度，破坏葡萄糖-胰岛素稳态，促进胎儿生长受限（FGR）。迄今为止，针对 FGR 的产前治疗尚未尝试同时纠正氧和葡萄糖供应。因此，我们研究了纠正 PI-FGR 胎儿的氧和葡萄糖浓度是否会使胰岛素分泌和葡萄糖代谢正常化。该实验在由母体发热诱导 PI 的接近足月的 FGR 胎羊中进行。通过增加母体吸入的氧气分数将胎儿动脉氧张力提高到正常水平，并向 FGR 胎儿输注葡萄糖（FGR-OG）。将 FGR-OG 胎儿与接受母体空气吹入、盐水输注的胎儿（FGR-AS）和对照胎儿进行比较。在治疗前，FGR 胎儿存在低氧血症和低血糖血症，并且葡萄糖刺激的胰岛素分泌（GSIS）减少。在治疗过程中，FGR-OG 胎儿的氧、葡萄糖和胰岛素浓度增加，去甲肾上腺素浓度降低，而 FGR-AS 胎儿则不受影响。在治疗第 4 天，通过正常血糖和高胰岛素正常血糖钳夹测量葡萄糖通量。在两个钳夹期间，FGR-AS 胎儿的葡萄糖利用和产生速率均高于 FGR-OG 胎儿，而 FGR-OG 胎儿的葡萄糖通量与对照速率无差异。治疗 5 天后，FGR-OG 胎儿的 GSIS 增加到对照水平，其离体胰岛的 GSIS 大于 FGR-AS 胰岛。尽管胎儿特征、GSIS 和葡萄糖通量正常化，但 FGR-OG 和 FGR-AS 胎儿的体重仍低于对照。这些发现表明，在 FGR 发生后，持续、同时纠正氧和葡萄糖使 PI-FGR 胎儿的 GSIS 和全身葡萄糖通量正常化。
