White Alicia, Stremming Jane, Wesolowski Stephanie R, Al-Juboori Saif I, Dobrinskikh Evgenia, Limesand Sean W, Brown Laura D, Rozance Paul J
University of Colorado, Aurora, Colorado, United States.
University of Arizona, Tucson, Arizona, United States.
Am J Physiol Endocrinol Metab. 2025 Jan 1;328(1):E116-E125. doi: 10.1152/ajpendo.00259.2024. Epub 2024 Dec 16.
Insulin-like growth factor-1 (IGF-1) and insulin are important fetal anabolic hormones. Complications of pregnancy, such as placental insufficiency, can lead to fetal growth restriction (FGR) with low-circulating IGF-1 and insulin concentrations and attenuated glucose-stimulated insulin secretion (GSIS), which likely contribute to neonatal glucose dysregulation. We previously demonstrated that a 1-wk infusion of IGF-1 LR3, an IGF-1 analog with low affinity for IGF-binding proteins and high affinity for the IGF-1 receptor, at 6.6 µg·kg·h into normal fetal sheep increased body weight but lowered insulin concentrations and GSIS. In this study, FGR fetal sheep received either IGF-1 LR3 treatment at 1.17 ± 0.12 μg·kg·h (LR3; = 7) or vehicle (VEH; = 7) for 1 wk. Plasma insulin, glucose, oxygen, and amino acids were measured before starting treatment and at the end of the treatment period. GSIS was measured on the final treatment day. Fetal body weights, insulin, glucose, oxygen, and GSIS were not different between groups. Amino acid concentrations decreased in LR3 (baseline vs. final individual means comparison = 0.0232) but not in VEH ( = 0.3866). In summary, a 1-wk IGF-1 LR3 treatment did not improve growth in FGR fetuses. Insulin concentrations and GSIS were not attenuated by IGF-1 LR3, yet circulating amino acids decreased, which could reflect increased amino acid utilization. We speculate that maintaining amino acid concentrations or raising insulin, glucose, and/or oxygen concentrations to values consistent with normally growing fetuses during IGF-1 LR3 treatment may be necessary to increase fetal growth in the setting of placental insufficiency and FGR. IGF-1 LR3 treatment administered directly into growth-restricted fetal sheep circulation did not improve fetal growth or attenuate circulating insulin or fetal GSIS. Importantly, IGF-1 LR3 treatment reduced circulating amino acids, notably branched-chain amino acids, which have been shown to potentiate GSIS and protein accretion supporting fetal growth.
胰岛素样生长因子-1（IGF-1）和胰岛素是重要的胎儿合成代谢激素。妊娠并发症，如胎盘功能不全，可导致胎儿生长受限（FGR），伴有循环中IGF-1和胰岛素浓度降低以及葡萄糖刺激的胰岛素分泌（GSIS）减弱，这可能导致新生儿血糖调节异常。我们之前证明，以6.6 μg·kg·h的剂量向正常胎儿绵羊静脉输注IGF-1 LR3（一种对IGF结合蛋白亲和力低而对IGF-1受体亲和力高的IGF-1类似物）1周，可增加体重，但会降低胰岛素浓度和GSIS。在本研究中，FGR胎儿绵羊接受1.17±0.12 μg·kg·h的IGF-1 LR3治疗（LR3组；n = 7）或赋形剂（VEH组；n = 7），持续1周。在开始治疗前和治疗期结束时测量血浆胰岛素、葡萄糖、氧气和氨基酸水平。在治疗的最后一天测量GSIS。两组之间的胎儿体重、胰岛素、葡萄糖、氧气和GSIS没有差异。LR3组氨基酸浓度降低（基线与最终个体均值比较，P = 0.0232），而VEH组未降低（P = 0.3866）。总之，1周的IGF-1 LR3治疗并未改善FGR胎儿的生长。IGF-1 LR3并未减弱胰岛素浓度和GSIS，但循环氨基酸减少，这可能反映了氨基酸利用增加。我们推测，在IGF-1 LR3治疗期间，将氨基酸浓度维持在正常生长胎儿的水平，或提高胰岛素、葡萄糖和/或氧气浓度，可能对于在胎盘功能不全和FGR情况下促进胎儿生长是必要的。直接注入生长受限胎儿绵羊循环的IGF-1 LR3治疗并未改善胎儿生长，也未减弱循环胰岛素或胎儿GSIS。重要的是，IGF-1 LR3治疗降低了循环氨基酸水平，尤其是支链氨基酸，而支链氨基酸已被证明可增强GSIS并促进支持胎儿生长的蛋白质积累。
