Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
J Dev Orig Health Dis. 2023 Jun;14(3):353-361. doi: 10.1017/S2040174423000090. Epub 2023 Apr 28.
Insulin-like growth factor-1 (IGF-1) is a critical fetal growth hormone that has been proposed as a therapy for intrauterine growth restriction. We previously demonstrated that a 1-week IGF-1 LR3 infusion into fetal sheep reduces and insulin secretion suggesting an intrinsic islet defect. Our objective herein was to determine whether this intrinsic islet defect was related to chronicity of exposure. We therefore tested the effects of a 90-min IGF-1 LR3 infusion on fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion from isolated fetal islets. We first infused late gestation fetal sheep ( = 10) with either IGF-1 LR3 (IGF-1) or vehicle control (CON) and measured basal insulin secretion and GSIS utilizing a hyperglycemic clamp. We then isolated fetal islets immediately following a 90-min IGF-1 or CON infusion and exposed them to glucose or potassium chloride to measure insulin secretion (IGF-1, = 6; CON, = 6). Fetal plasma insulin concentrations decreased with IGF-1 LR3 infusion ( < 0.05), and insulin concentrations during the hyperglycemic clamp were 66% lower with IGF-1 LR3 infusion compared to CON ( < 0.0001). Insulin secretion in isolated fetal islets was not different based on infusion at the time of islet collection. Therefore, we speculate that while acute IGF-1 LR3 infusion may directly suppress insulin secretion, the fetal β-cell retains the ability to recover GSIS. This may have important implications when considering the long-term effects of treatment modalities for fetal growth restriction.
胰岛素样生长因子-1（IGF-1）是一种重要的胎儿生长激素，它被提议作为治疗宫内生长受限的一种方法。我们之前的研究表明，在胎儿羊中进行为期一周的 IGF-1 LR3 输注可减少 和 胰岛素分泌，这表明胰岛存在内在缺陷。我们的目标是确定这种内在胰岛缺陷是否与暴露的慢性有关。因此，我们测试了 IGF-1 LR3 90 分钟输注对胎儿葡萄糖刺激的胰岛素分泌（GSIS）和分离的胎儿胰岛胰岛素分泌的影响。我们首先用 IGF-1 LR3（IGF-1）或载体对照（CON）输注晚期妊娠胎儿羊（ = 10），并使用高血糖钳夹测量基础胰岛素分泌和 GSIS。然后，我们在 IGF-1 或 CON 输注 90 分钟后立即分离胎儿胰岛，并将其暴露于葡萄糖或氯化钾中以测量 胰岛素分泌（IGF-1， = 6；CON， = 6）。IGF-1 LR3 输注后胎儿血浆胰岛素浓度降低（ < 0.05），与 CON 相比，IGF-1 LR3 输注时高血糖钳夹期间的胰岛素浓度降低了 66%（ < 0.0001）。根据胰岛采集时的输注情况，分离的胎儿胰岛的胰岛素分泌没有差异。因此，我们推测，虽然急性 IGF-1 LR3 输注可能直接抑制胰岛素分泌，但胎儿 β 细胞 仍然能够恢复 GSIS。当考虑治疗胎儿生长受限的方法的长期影响时，这可能具有重要意义。
