Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets
Alicia White et al. J Dev Orig Health Dis. 2023 Jun.
Abstract
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 in vivo and in vitro 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 (n = 10) with either IGF-1 LR3 (IGF-1) or vehicle control (CON) and measured basal insulin secretion and in vivo GSIS utilizing a hyperglycemic clamp. We then isolated fetal islets immediately following a 90-min IGF-1 or CON in vivo infusion and exposed them to glucose or potassium chloride to measure in vitro insulin secretion (IGF-1, n = 6; CON, n = 6). Fetal plasma insulin concentrations decreased with IGF-1 LR3 infusion (P < 0.05), and insulin concentrations during the hyperglycemic clamp were 66% lower with IGF-1 LR3 infusion compared to CON (P < 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 in vitro retains the ability to recover GSIS. This may have important implications when considering the long-term effects of treatment modalities for fetal growth restriction.
Keywords: fetus; glucose-stimulated insulin secretion; insulin-like growth factor; β-cell.
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Conflict of interest statement
Competing interests: The authors declare none.
Conflicts of Interest: None.
Figures Figure 1.. Plasma insulin decreases with IGF-1 LR3 infusion.
Fetal plasma insulin (A) decreases with IGF-1 but not with CON infusion. Glucose (B) started lower with CON infusion but was similar to IGF-1 by the end of infusion. Endogenous IGF-1 concentrations (C) did not change based on infusion. CON, control infusion (open circles, n=10); IGF-1, IGF-1 LR3 infusion (closed squares, n=10). Means ± SEM 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. *Indicates P<0.05 and **indicates P<0.01 for individual means comparisons. Figure 2.. Glucose stimulated insulin secretion (GSIS) is attenuated with a 90-minute IGF-1 LR3 infusion.
Fetal plasma glucose (A) and insulin (B) during measurement of GSIS are plotted relative to the start of the hyperglycemic clamp at time 0. CON, control infusion (open circles, n=10); IGF-1, IGF-1 LR3-infusion (closed squares, n=10). Group means ± SEM 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. ***Indicates P<0.0001 for individual means comparisons. Figure 3.. Basal insulin secretion is not different based on infusion at necropsy.
Pancreatic islets isolated from control-infused (CON, open symbols, n=6) and IGF-1 LR3-infused (IGF-1, closed symbols, n=6) fetuses were evaluated for basal insulin secretion. One additional animal was included for islet studies to receive CON (open triangle), and another was included to receive IGF-1 LR3 infusion (closed triangle) at time of necropsy to increase the power to detect differences in islet insulin secretion. Means ± SEM are shown. Statistical analysis was performed by Student’s t-test. Figure 4.. Glucose stimulated insulin secretion is not different in isolated fetal islets exposed to IGF-1 in vivo at the time of necropsy.
Pancreatic islets isolated from control-infused (CON, open symbols, n=6) and IGF-1 LR3-infused (IGF-1, closed symbols, n=6) fetuses at time of necropsy were tested for fractional insulin release in Krebs-Ringer bicarbonate buffer with 1.1, 2.7, or 11 mmol·L−1 glucose, or 30 mmol·L−1 KCl for one hour. One additional animal was included for islet studies to receive CON (open triangle), and another was included to receive IGF-1 LR3 infusion (closed triangle) at time of necropsy to increase the power to detect differences in islet insulin secretion. Means ± SEM are shown. Statistical analysis was performed by mixed-model ANOVA.
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