Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for one week into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n=8), an analogue of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n=9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n=8; CON, n=7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n=8; CON, n=7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared to CON (P=0.0135 and P=0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared to CON (P=0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P=0.0447). In summary, IGF-1 LR3 infusion for one week into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for one week. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.

中文翻译：

---

在妊娠晚期胎羊中输注一周 IGF-1 后葡萄糖刺激的胰岛素分泌减少是由于固有的胰岛缺陷

胰岛素和胰岛素样生长因子-1 (IGF-1) 是对建立正常胎儿生长至关重要的胎儿激素。在妊娠晚期实验性升高的 IGF-1 浓度会增加胎儿体重，但会降低胎儿血浆胰岛素浓度。因此，我们假设将 IGF-1 类似物输注到妊娠晚期胎羊中一周会减弱胎儿葡萄糖刺激的胰岛素分泌 (GSIS) 和从这些胎儿分离的胰岛中的胰岛素分泌。妊娠晚期胎羊接受输注 IGF-1 LR3 (IGF-1, n=8)，一种对 IGF 结合蛋白具有低亲和力和对 IGF-1 受体具有高亲和力的 IGF-1 类似物，或载体对照 (CON , n = 9)。胎儿 GSIS 用高血糖钳 (IGF-1, n=8; CON, n=7) 测量。分离出胎儿胰岛，在静态孵育中测定胰岛素分泌（IGF-1，n=8；CON，n=7）。与 CON 相比，IGF-1 胎儿的血浆胰岛素和葡萄糖浓度较低（分别为 P = 0.0135 和 P = 0.0012）。在 GSIS 研究期间，与 CON 相比，IGF-1 胎儿的胰岛素分泌较低（P=0.0453）。在体外，从 IGF-1 胎儿分离的胰岛中，葡萄糖刺激的胰岛素分泌仍然较低（P=0.0447）。总之，将 IGF-1 LR3 输注到胎羊中 1 周可降低胰岛素浓度并降低胎儿 GSIS。当暴露于 IGF-1 LR3 输注一周时，孤立的胎儿胰岛中持续存在胰岛素分泌受损，表明胰岛素释放存在内在的胰岛缺陷。