Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

• Published in: Scientific reports Vol. 10; no. 1; p. 5609
• Main Authors: Jensen, Vivi F. H., Mølck, Anne-Marie, Bøgh, Ingrid B., Nowak, Jette, Viuff, Birgitte M., Rasmussen, Charlotte L. M., Pedersen, Louise, Fels, Johannes J., Madsen, Suzi H., McGuigan, Fiona E., Tveden-Nyborg, Pernille, Lykkesfeldt, Jens, Akesson, Kristina E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.03.2020
• Subjects: 631/1647; 631/1647/2017; 631/1647/245; 631/1647/328; 631/1647/767; Animals; Cell Differentiation - physiology; Chondrocytes - metabolism; Chondrocytes - pathology; Clinical Medicine; Corticosterone - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Fetal Development - physiology; Fetus - metabolism; Fetus - pathology; Growth Plate - metabolism; Growth Plate - pathology; Humanities and Social Sciences; Hypoglycemia - metabolism; Hypoglycemia - pathology; Hypoxia - metabolism; Hypoxia - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; multidisciplinary; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Pregnancy; Prenatal Care - methods; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Vascular Endothelial Growth Factor A - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-62554-2

Maternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.