Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats
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Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats. / Jensen, Vivi Flou Hjorth; Mølck, Anne Marie; Lykkesfeldt, Jens; Fels, Johannes Josef; Andersen, Lene; Renaut, Ruth; McGuigan, Fiona; Åkesson, Kristina E.; Bøgh, Ingrid Brück.
I: Reproductive Toxicology, Bind 91, 2020, s. 14-26.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats
AU - Jensen, Vivi Flou Hjorth
AU - Mølck, Anne Marie
AU - Lykkesfeldt, Jens
AU - Fels, Johannes Josef
AU - Andersen, Lene
AU - Renaut, Ruth
AU - McGuigan, Fiona
AU - Åkesson, Kristina E.
AU - Bøgh, Ingrid Brück
PY - 2020
Y1 - 2020
N2 - The aim was to investigate embryo-foetal effects of continuous maternal insulin-induced hypoglycaemia extending throughout gestation or until gestation day (GD)17 (typical last day of dosing during pre-clinical evaluation) providing comparator data for safety assessment of longer-acting insulin analogues in non-diabetic rats. Pregnant rats received human insulin (HI)-infusion during gestation until either GD20 or GD17 (HI-GD20; HI-GD17). On GD20, foetal abnormalities and skeletal ossification/mineralisation were evaluated. HI-infusion induced continuous hypoglycaemia. Foetal skeletal and eye malformations (e.g. bent ribs, microphthalmia) were common in both groups. Foetal size and skeletal ossification/mineralisation decreased, particularly with infusion throughout gestation. Concluding, insulin-induced hypoglycaemia during gestation in non-diabetic rats is damaging to embryo-foetal growth and skeletal development, particularly after GD17. Three days without HI-infusion after GD17 allows for some developmental catch-up. Eye development is sensitive to HI-infusion before GD17. These results should serve as a benchmark during pre-clinical safety assessment of longer-acting insulin analogues tested in rats.
AB - The aim was to investigate embryo-foetal effects of continuous maternal insulin-induced hypoglycaemia extending throughout gestation or until gestation day (GD)17 (typical last day of dosing during pre-clinical evaluation) providing comparator data for safety assessment of longer-acting insulin analogues in non-diabetic rats. Pregnant rats received human insulin (HI)-infusion during gestation until either GD20 or GD17 (HI-GD20; HI-GD17). On GD20, foetal abnormalities and skeletal ossification/mineralisation were evaluated. HI-infusion induced continuous hypoglycaemia. Foetal skeletal and eye malformations (e.g. bent ribs, microphthalmia) were common in both groups. Foetal size and skeletal ossification/mineralisation decreased, particularly with infusion throughout gestation. Concluding, insulin-induced hypoglycaemia during gestation in non-diabetic rats is damaging to embryo-foetal growth and skeletal development, particularly after GD17. Three days without HI-infusion after GD17 allows for some developmental catch-up. Eye development is sensitive to HI-infusion before GD17. These results should serve as a benchmark during pre-clinical safety assessment of longer-acting insulin analogues tested in rats.
KW - Embryo-foetal development
KW - Human insulin
KW - Hypoglycaemia
KW - Pre-clinical
KW - Toxicology
U2 - 10.1016/j.reprotox.2019.10.003
DO - 10.1016/j.reprotox.2019.10.003
M3 - Journal article
C2 - 31644949
AN - SCOPUS:85074344927
VL - 91
SP - 14
EP - 26
JO - Reproductive Toxicology
JF - Reproductive Toxicology
SN - 0890-6238
ER -
ID: 234210000