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

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

doi:10.1016/j.reprotox.2019.10.003

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

Reprod Toxicol. 2020 Jan:91:14-26. doi: 10.1016/j.reprotox.2019.10.003. Epub 2019 Oct 20.

Authors

Vivi Flou Hjorth Jensen¹, Anne-Marie Mølck², Jens Lykkesfeldt³, Johannes Josef Fels⁴, Lene Andersen⁵, Ruth Renaut⁶, Fiona McGuigan⁷, Kristina E Åkesson⁷, Ingrid Brück Bøgh²

Affiliations

¹ Department of Toxicology Development Projects, Novo Nordisk A/S Maaloev, Denmark; Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Sciences Malmö, Clinical and Molecular Osteoporosis Research Unit, Lund University, Malmö, Sweden; Department of Orthopedics, Skåne University, Malmö, Sweden. Electronic address: vivi_flou_hjorth.jensen@med.lu.se.
² Department of Toxicology Development Projects, Novo Nordisk A/S Maaloev, Denmark.
³ Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, University of Copenhagen, Copenhagen, Denmark.
⁴ Department of Research Bioanalysis, Novo Nordisk A/S, Maaloev, Denmark.
⁵ Department of Clinical Bioanalysis, Novo Nordisk A/S, Maaloev, Denmark.
⁶ Division of Toxicology, Envigo, Eye, Suffolk, UK.
⁷ Department of Clinical Sciences Malmö, Clinical and Molecular Osteoporosis Research Unit, Lund University, Malmö, Sweden; Department of Orthopedics, Skåne University, Malmö, Sweden.

PMID: 31644949
DOI: 10.1016/j.reprotox.2019.10.003

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, 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.

Keywords: Embryo-foetal development; Human insulin; Hypoglycaemia; Pre-clinical; Toxicology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / analysis
Bone and Bones / abnormalities*
Embryo, Mammalian / abnormalities
Embryonic Development*
Eye Abnormalities*
Female
Fetal Development*
Hypoglycemia / chemically induced
Hypoglycemia / complications*
Insulin
Male
Maternal-Fetal Exchange
Osteogenesis
Pregnancy
Rats, Sprague-Dawley

Substances

Blood Glucose
Insulin