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

Jensen, Vivi Flou Hjorth LU ; Mølck, Anne Marie ; Lykkesfeldt, Jens ; Fels, Johannes Josef ; Andersen, Lene ; Renaut, Ruth ; McGuigan, Fiona LU orcid ; Åkesson, Kristina E. LU and Bøgh, Ingrid Brück (2020) In Reproductive Toxicology 91. p.14-26
Abstract

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,... (More)

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.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Embryo-foetal development, Human insulin, Hypoglycaemia, Pre-clinical, Toxicology
in
Reproductive Toxicology
volume
91
pages
13 pages
publisher
Elsevier
external identifiers
  • pmid:31644949
  • scopus:85074344927
ISSN
0890-6238
DOI
10.1016/j.reprotox.2019.10.003
language
English
LU publication?
yes
id
1f90583a-49cf-4b6e-94e8-8c6cfce1f767
date added to LUP
2021-01-15 10:23:07
date last changed
2024-06-13 05:20:42
@article{1f90583a-49cf-4b6e-94e8-8c6cfce1f767,
  abstract     = {{<p>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.</p>}},
  author       = {{Jensen, Vivi Flou Hjorth and Mølck, Anne Marie and Lykkesfeldt, Jens and Fels, Johannes Josef and Andersen, Lene and Renaut, Ruth and McGuigan, Fiona and Åkesson, Kristina E. and Bøgh, Ingrid Brück}},
  issn         = {{0890-6238}},
  keywords     = {{Embryo-foetal development; Human insulin; Hypoglycaemia; Pre-clinical; Toxicology}},
  language     = {{eng}},
  pages        = {{14--26}},
  publisher    = {{Elsevier}},
  series       = {{Reproductive Toxicology}},
  title        = {{Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats}},
  url          = {{http://dx.doi.org/10.1016/j.reprotox.2019.10.003}},
  doi          = {{10.1016/j.reprotox.2019.10.003}},
  volume       = {{91}},
  year         = {{2020}},
}