A 1 week IGF-1 infusion decreases arterial insulin concentrations but increases pancreatic insulin content and islet vascularity in fetal sheep

White, Alicia; Louey, Samantha; Chang, Eileen I.; Boehmer, Brit H; Goldstrohm, David A.; Jonker, Sonnet S.; Rozance, Paul J.

doi:10.14814/phy2.13840

Cited by 6 publications

(11 citation statements)

References 49 publications

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“…In this study, we demonstrated that oIGF-1, like LR3 IGF-1 ( Stremming et al, 2021 ), increased in vitro myoblast proliferation, in vivo myoblast proliferation, and selective fetal organ weight, but it did not increase fetal body weight. Similar to infusion of LR3 IGF-1, fetal oIGF-1 infusion for 1 week also attenuated fetal insulin concentrations, which has been previously reported ( Liechty et al, 1996 ; Lok et al, 1996 ; Boyle et al, 1998 ; White et al, 2018 ; Stremming et al, 2021 ; White et al, 2021 ); however, fetal glucose concentrations in oIGF-1 are maintained similar to control animals. Fetal plasma amino acid concentrations were also lower after infusion of oIGF-1, which is consistent with infusion of LR3 IGF-1 ( Stremming et al, 2021 ).…”

Section: Discussionsupporting

confidence: 82%

“…At the end of the infusion period, fetal IGF-1 concentrations were 3.5-fold higher in oIGF-1 infused fetuses compared to saline infused fetuses ( Figure 3B ). Because IGF-1 infusion decreases fetal insulin concentrations ( Liechty et al, 1996 ; Lok et al, 1996 ; Boyle et al, 1998 ; White et al, 2018 ; Stremming et al, 2021 ; White et al, 2021 ), plasma insulin concentrations were obtained. At the end of the infusion period, fetal plasma insulin concentrations were 89% lower in oIGF-1 infused fetuses compared to fetuses that received a saline infusion ( Figure 3C ).…”

Section: Resultsmentioning

confidence: 99%

“…One possibility may involve concurrent downregulation of insulin concentrations and potential synergy with amino acid supply and metabolism. LR3 IGF-1 infusion decreases fetal insulin and amino acid concentrations ( Liechty et al, 1996 ; Lok et al, 1996 ; Boyle et al, 1998 ; White et al, 2018 ; Stremming et al, 2021 ; White et al, 2021 ), which may limit fetal growth potential. Consistent with previous studies, we also demonstrated that fetal insulin concentrations were reduced after infusion of oIGF-1 for 1 week.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact mechanism to explain reduced insulin concentrations after IGF-1 infusion is not well understood, our lab has previously shown that infusion of LR3 IGF-1 attenuates glucose stimulated insulin secretion in vivo and islet cell secretion of insulin in vitro ( White et al, 2021 ). Pancreatic insulin content is also increased, suggesting an inhibition of insulin secretion rather than production ( White et al, 2018 ). Fetal arterial glucose, lactate, and oxygen concentrations were unchanged in oIGF-1 infused fetuses after a 1-week infusion.…”

Section: Discussionmentioning

confidence: 99%

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Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep

et al. 2022

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IGF-1 is a critical fetal growth-promoting hormone. Experimental infusion of an IGF-1 analog, human recombinant LR3 IGF-1, into late gestation fetal sheep increased fetal organ growth and skeletal muscle myoblast proliferation. However, LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), thus reducing physiologic regulation of IGF-1 bioavailability. The peptide sequences for LR3 IGF-1 and sheep IGF-1 also differ. To overcome these limitations with LR3 IGF-1, we developed an ovine (sheep) specific recombinant IGF-1 (oIGF-1) and tested its effect on growth in fetal sheep. First, we measured in vitro myoblast proliferation in response to oIGF-1. Second, we examined anabolic signaling pathways from serial skeletal muscle biopsies in fetal sheep that received oIGF-1 or saline infusion for 2 hours. Finally, we measured the effect of fetal oIGF-1 infusion versus saline infusion (SAL) for 1 week on fetal body and organ growth, in vivo myoblast proliferation, skeletal muscle fractional protein synthetic rate, IGFBP expression in skeletal muscle and liver, and IGF-1 signaling pathways in skeletal muscle. Using this approach, we showed that oIGF-1 stimulated myoblast proliferation in vitro. When infused for 1 week, oIGF-1 increased organ growth of the heart, kidney, spleen, and adrenal glands and stimulated skeletal myoblast proliferation compared to SAL without increasing muscle fractional synthetic rate or hindlimb muscle mass. Hepatic and muscular gene expression of IGFBPs one to three was similar between oIGF-1 and SAL. We conclude that oIGF-1 promotes tissue and organ-specific growth in the normal sheep fetus.

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep

et al. 2022

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“…Postnatal myocyte proliferation occurs in skeletal muscle through the engagement and fusion of satellite cells, but cardiac myocyte number is determined prenatally, with minimal regenerative capacity even in the context of injury (White et al, 2018;Yin et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Changes in microvascular perfusion of heart and skeletal muscle in sheep around the time of birth

Hagen

Louey

Alaniz

et al. 2022

Experimental Physiology

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New Findings What is the central question of this study?How does the microvascular perfusion of striated muscle change during the dynamic developmental period between the late gestation fetus and early neonate? What is the main finding and its importance?In both myocardium and skeletal muscle, perfusion of striated muscle is significantly reduced in the neonate compared to the late term fetus, but flow reserve is unchanged. The results suggest striated muscle capillary networks grow more slowly relative to the myofibres they nourish during the perinatal period. Abstract Microvascular perfusion of striated muscle is an important determinant of health throughout life. Birth is a transition with profound effects on the growth and function of striated muscle, but the regulation of microvascular perfusion around this transition is poorly understood. We used contrast‐enhanced ultrasound perfusion imaging (CEUS) to study the perfusion of left ventricular myocardium and hindlimb biceps femoris, which are populations of muscle with different degrees of change in pre‐ to postnatal workloads and different capacities for postnatal proliferative growth. We studied separate groups of lambs in late gestation (135 days’ gestational age; 92% of term) and shortly after birth (5 days’ postnatal age). We used CEUS to quantify baseline perfusion, perfusion during hyperaemia induced by adenosine infusion (myocardium) or electrically stimulated unloaded exercise (skeletal muscle), flow reserve and oxygen delivery. We found heart‐to‐body weight ratio was greater in neonates than fetuses. Microvascular volume and overall perfusion were lower in neonates than fetuses in both muscle groups at baseline and with hyperaemia. Flux rate differed with muscle group, with myocardial flux being faster in neonates than fetuses, but skeletal muscle flux being slower. Oxygen delivery to skeletal muscle at baseline was lower in neonates than fetuses, but was not significantly different in myocardium. Flow reserve was not different between ages. Given the significant somatic growth, and the transition from hyperplastic to hypertrophic myocyte growth occurring in the perinatal period, we postulate that the primary driver of lower neonatal striated muscle perfusion is faster growth of myofibres than their associated capillary networks.

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Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets

White

Stremming

Brown

et al. 2023

J Dev Orig Health Dis

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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.

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A 1 week IGF-1 infusion decreases arterial insulin concentrations but increases pancreatic insulin content and islet vascularity in fetal sheep

Cited by 6 publications

References 49 publications

Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep

Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep

Changes in microvascular perfusion of heart and skeletal muscle in sheep around the time of birth

Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets

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