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

Publication date: Available online 20 October 2019Source: Reproductive ToxicologyAuthor(s): Vivi Flou Hjorth Jensen, Anne-Marie Mølck, Jens Lykkesfeldt, Johannes Josef Fels, Lene Andersen, Ruth Renaut, Fiona McGuigan, Kristina E. Åkesson, Ingrid Brück BøghAbstractThe 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.
Source: Reproductive Toxicology - Category: Toxicology Source Type: research