Progenies of gestational diabetes mellitus exhibit sex disparity in metabolism after respective therapies of insulin, glibenclamide, and metformin in dams during pregnancy

Abstract

Background

The aim of this study was to compare the sex-dependent intergenerational effects of insulin, glibenclamide, and metformin on glucose and lipid metabolism in the offspring born to GDM mice.

Methods

The murine GDM was induced by high fat diet. The offspring were grouped based on the treatments in maternal mice. ITT and GTT were performed at 4th and 8th weeks of age, respectively. Serum levels of TC, TG, HDL-C, and LDL-C plus hepatic levels of TG and TC, were respectively determined by enzymatic kits. Western blotting was conducted to detect related proteins in the livers from offspring.

Results

The dyslipidaemia, hepatic lipid abnormality, and insulin insensitivity caused by GDM were persistently normalised in male adult offspring by the respective therapies of insulin, glibenclamide, and metformin during maternal pregnancy. Specifically, the decreases in plasma TC, TG, and LDL-C levels (29%, 37.8%, and 57.7%, respectively, p ˂ .05) and in hepatic lipid contents (TC 31.3% and TG 39.2%, p ˂ .05), the increases in hepatic phosphorylation levels of AKT, CPT1A, PPAR-α, and PPAR-γ (57.1%, 91.7%, 68%, and 173.3%, respectively, p ˂ .05) and the inhibition of G6Pase, PEPCK, and HMGCS1 (35.7%, 68.8%, and 77.3% respectively, p ˂ .05) were still observed in the male offspring born to treated GDM mice from 4th to 8th week of age. Unexpectedly, the aforementioned parameters in female progenies in different groups were not significantly changed compared with controls.

Conclusions

Respective treatments in GDM mice during pregnancy with insulin, glibenclamide, and metformin have the long-term persistent effects in male offspring, while female progenies born to untreated dams showed an autonomous inhibition of intergenerational relay of glucose and lipid dysregulation. Our current findings may imply a sex-dependent strategy of medical care for GDM mothers and their offspring.

Novelties

• Respective interventions of insulin, glibenclamide, and metformin on dams exerted the persisted effects on male progenies.

• Therapies of three drugs on dams had the similarly improved effects in offspring.

• Female offspring autonomously corrected their dysregulated glucose-lipid metabolism caused by gestational diabetes mellitus (GDM) in dams.

Keywords:

• GDM
• offspring
• glibenclamide
• metformin
• glucose and lipid metabolism

Acknowledgements

The authors thank all the participants in this study.

Ethics approval and consent to participate

Animal procedures were approved by the Animal Care and Use Committee, faculty of Science, Anhui Medical University, in accordance with the International Guidance principles for Biomedical Research Involving animals of CIOMS.

Consent for publication

All authors listed have approved the manuscript for publication.

Disclosure statement

The authors declared no conflicts of interest.

Availability of data and materials

All data in this study are available from the corresponding author on reasonable request.

Supplemental Material available at: DOI: https://doi.org/10.6084/m9.figshare.14617119 URL: https://figshare.com/s/c8fa04af4e7dc6f86676

Author contributions

K.C and Y. L designed the research, provide financial support and revised/edited the manuscript; Y.L, Y.X provided partial research fund; Y. L^#, Y.J, and J.L performed all experiments; J.L analysed the data; Y. L^# and Y.J wrote the draft of manuscript.

Additional information

Funding

This work is supported by the National Natural Science Foundation of China [NSFC, 81570786 to K.C, 81770295 to Y.L], and The Key Research and Development Project of Anhui province of China [201904d07020003 to Y. X].