Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats

Jensen, Vivi Flou Hjorth; Mølck, Anne Marie; Lykkesfeldt, Jens; Fels, Johannes; Andersen, Lene Frost; Renaut, Ruth; McGuigan, Fiona; Åkesson, Kristina; Bøgh, Ingrid Brück

doi:10.1016/j.reprotox.2019.10.003

Cited by 5 publications

(21 citation statements)

References 39 publications

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“…Hypoglycaemia throughout gestation decreased total growth plate volume as anticipated based on previously observed shortened tibia length in litter-mates (foetuses from the same litters used for other investigations) 6 , which are known effects of glucocorticoid-dosing in rats and rabbits [32][33][34] . The disproportionate zone volume changes may be linked to reduced local VEGF-A levels.…”

Section: Discussionsupporting

confidence: 69%

“…Decreased MATN-3 expression may also be implicated, since MATN-3 KO promotes chondrocyte hypertrophy in mouse embryos 10,36 ; this is reflected by an increased hypertrophic zone length in tibial growth plates following premature maturation of proliferative into hypertrophic chondrocytes 10 . In contrast to hypoglycaemia lasting throughout gestation, hypoglycaemia ending on GD17 resulted in only slightly decreased total and separate growth plate volumes, which were not statistically different from controls; this was surprising given the shorter tibial length in litter-mates 6 . However, since this decrease in tibial length was less pronounced than after hypoglycaemia throughout gestation 6 , it possibly reflects delayed bone growth prior to GD17 extending beyond GD17, allowing only for an attenuation of the decrease.…”

Section: Discussionmentioning

confidence: 80%

“…We have previously used HI-infusion in a pregnant non-diabetic rat model to investigate the effects from continuous hypoglycaemia on foetal skeletal development. We showed that maternal hypoglycaemia throughout gestation delays foetal growth and skeletal development, while hypoglycaemia only until after completion of organogenesis (GD17) allows for near-normal development 6 . The mechanisms underlying these developmental changes are not fully understood.…”

Section: Discussionmentioning

confidence: 96%

“…Previously we showed that continuous maternal hypoglycaemia throughout gestation resulted in skeletal malformations, as well as decreased skeletal growth and bone mineral density 5 . In comparison hypoglycaemia lasting only until GD17, when organogenesis is completed, followed by normoglycemia allowed for near-normal development, emphasising that sufficient glucose supply late in gestation is crucial 6 .…”

mentioning

confidence: 99%

“…The investigational strategy builds on our animal model of maternal hypoglycaemia induced by continuous infusion with human insulin (HI) lasting either throughout gestation until termination on GD20 or until GD17 (covering the embryonic period and organogenesis), followed by three days without insulin-infusion (GD17-20) 6 .…”

mentioning

confidence: 99%

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

Jensen

Mølck

Bøgh

et al. 2020

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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.

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