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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Embryo-foetal development

Human insulin

Hypoglycaemia

Pre-clinical

Toxicology

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