IGF-1 LR3 does not promote growth in late-gestation growth-restricted fetal sheep
Alicia White et al. Am J Physiol Endocrinol Metab. 2025.
Abstract
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-1·h-1 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-1·h-1 (LR3; n = 7) or vehicle (VEH; n = 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 P = 0.0232) but not in VEH (P = 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.NEW & NOTEWORTHY 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.
Keywords: fetal growth restriction; fetal pancreas; insulin; insulin-like growth factor-1.
Copyright © 2025 The Authors.
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Conflict of interest statement
No conflicts of interest, financial or otherwise, are declared by the authors.
Figures Graphical abstract Figure 1.
Plasma insulin, glucose, O2 content, and endogenous IGF-1 did not change in either group. Fetal plasma insulin (A), glucose (B), O2 content (C), and endogenous IGF-1 concentrations (D) did not change over time based on treatment. VEH, vehicle (male, open circles; female, open triangles; n = 7 fetuses); LR3, IGF-1 LR3 (male, closed circles; female, closed triangles; n = 7 fetuses). Means ± SE are shown. Statistical analysis was performed by mixed-model ANOVA; protected Fisher’s least significant difference test was performed for individual means comparisons if interaction P < 0.1 and labeled if P < 0.05. Figure 2.
Plasma amino acids decreased with IGF-1 LR3 treatment. Summed total amino acids (A), summed nonessential amino acids (B), and summed essential amino acids (C) decreased in fetuses receiving IGF-1 LR3 but not in those receiving vehicle. VEH, vehicle (male, open circles; female, open triangles; n = 7 fetuses); LR3, IGF-1 LR3 (male, closed circles; female, closed triangles; n = 7 fetuses). Means ± SE are shown. Statistical analysis was performed by mixed-model ANOVA; protected Fisher’s least significant difference test was performed for individual means comparisons if interaction P < 0.1 and labeled if P < 0.05. Figure 3.
Glucose-stimulated insulin secretion (GSIS) is not different based on treatment. Fetal plasma glucose (A) and insulin (B) during measurement of GSIS are plotted relative to the start of the hyperglycemic clamp at time 0. VEH, vehicle (open circles, n = 7 fetuses); LR3, IGF-1 LR3 (closed squares, n = 7 fetuses). Means ± SE are shown. Statistical analysis was performed by mixed-model ANOVA.
References
Christou H, Connors JM, Ziotopoulou M, Hatzidakis V, Papathanassoglou E, Ringer SA, Mantzoros CS. Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth. J Clin Endocrinol Metab 86: 935–938, 2001. doi: 10.1210/jcem.86.2.7217. - DOI - PubMed
Ostlund E, Bang P, Hagenäs L, Fried G. Insulin-like growth factor I in fetal serum obtained by cordocentesis is correlated with intrauterine growth retardation. Hum Reprod 12: 840–844, 1997. doi: 10.1093/humrep/12.4.840. - DOI - PubMed
Lassarre C, Hardouin S, Daffos F, Forestier F, Frankenne F, Binoux M. Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 29: 219–225, 1991. doi: 10.1203/00006450-199103000-00001. - DOI - PubMed
Green AS, Rozance PJ, Limesand SW. Consequences of a compromised intrauterine environment on islet function. J Endocrinol 205: 211–224, 2010. [Erratum in J Endocrinol 206: 335, 2010]. doi: 10.1677/JOE-09-0399. - DOI - PMC - PubMed
Boehmer BH, Limesand SW, Rozance PJ. The impact of IUGR on pancreatic islet development and β-cell function. J Endocrinol 235: R63–R76, 2017. doi: 10.1530/JOE-17-0076. - DOI - PMC - PubMed
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