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Title: Clinical outcome and gut development after insulin-like growth factor-1 supplementation to preterm pigs

Author
item HOLGERSEN, KRISTINE - University Of Copenhagen
item RASMUSSEN, MARTIN - University Of Copenhagen
item CAREY, GALEN - Baylor College Of Medicine
item Burrin, Douglas - Doug
item THYMANN, THOMAS - University Of Copenhagen
item SANGILD, PER TORP - University Of Copenhagen

Submitted to: Frontiers in Pediatrics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/8/2022
Publication Date: 8/5/2022
Citation: Holgersen, K., Rasmussen, M.B., Carey, G., Burrin, D.G., Thymann, T., Sangild, P. 2022. Clinical outcome and gut development after insulin-like growth factor-1 supplementation to preterm pigs. Frontiers in Pediatrics. https://doi.org/10.3389/fped.2022.868911.
DOI: https://doi.org/10.3389/fped.2022.868911

Interpretive Summary: The survival rates of very premature infants are increasing but many of these infants experience several medical conditions and poor growth in the months after birth. Premature infants are at increased risk for an intestinal disease called necrotizing enterocolitis (NEC). Insulin-like growth factor-1 (IGF-1) is a key hormone involved in the regulation of infant growth and organ development. Premature infants have a sustained period of low plasma IGF-1 levels after birth and these low levels correlate directly with poor growth. Importantly, IGF-1 is present in human breast milk and absent in infant formula and breast milk feeding reduces the risk of NEC in premature infants. We previously showed that premature neonatal piglets have low plasma IGF-1 after birth and intravenous administration of IGF-1 fused with a binding protein (IGFBP-3) would restore normal IGF-1 blood levels. In this study, we tested different dosing regimens of either longer-term, intermittent and shorter term, continuous dosing on gut, metabolism and additional immune–related outcomes. The current study shows that IGF-1 administration increased intestinal growth, protein synthesis and reduced the severity of NEC compared to piglets given control treatment. These results provide further evidence for the safe and efficacious therapeutic use IGF-1 in the early postnatal period in preterm infants.

Technical Abstract: Elevation of circulating insulin-like growth factor-1 (IGF-1) within normal physiological levels may alleviate several morbidities in preterm infants but safety and efficacy remain unclear. We hypothesized that IGF-1 supplementation during the first 1-2 weeks after preterm birth improves clinical outcomes and gut development, using preterm pigs as a model for infants. Preterm pigs were given vehicle or recombinant human IGF-1/binding protein-3 (rhIGF-1, 2.25 mg/kg/d) by subcutaneous injections for 8 days (Experiment 1, n=34), or by systemic infusion for 4 days (Experiment 2, n=18), before collection of blood and organs for analyses. In both experiments, rhIGF-1 treatment increased plasma IGF-1 levels 3-4 fold, reaching the values reported for term suckling piglets. In Experiment 1, rhIGF-1 treatment increased spleen and intestinal weights without affecting clinical outcomes like growth, blood biochemistry (except increased sodium and gamma-glutamyltransferase levels), hematology (e.g. red and white blood cell populations), glucose homeostasis (e.g. basal and glucose-stimulated insulin and glucose levels) or systemic immunity variables (e.g. T cell subsets, neutrophil phagocytosis, LPS stimulation, bacterial translocation to bone marrow). The rhIGF-1 treatment increased gut protein synthesis (+11%, p<0.05), reduced the combined incidence of all-cause mortality and severe necrotizing enterocolitis (NEC, p<0.05), but had limited effects on intestinal morphology, cell proliferation, cell apoptosis, brush-border disaccharidase and peptidase activities, permeability and levels of cytokines (IL-1Beta, IL-6, IL-8). In Experiment 2, rhIGF-1 treated pigs had reduced blood creatine kinase, creatinine, potassium and aspartate aminotransferase levels, with no effects on organ weights (except increased spleen weight), blood chemistry values, clinical variables or NEC. Physiological elevation of systemic IGF-1 levels for eight days after preterm birth increased intestinal weight/protein synthesis, spleen weight and potential overall viability of pigs, without any apparent negative effects on recorded clinical parameters. The results add further preclinical support for safety and efficacy of supplemental IGF-1 to hospitalized very preterm infants.