Maternal but not fetoplacental health can be improved by metformin in a murine diet-induced model of maternal obesity and glucose intolerance.

Antonia Hufnagel,Thomas J Ashmore,Susan E Ozanne,Heather L Blackmore,Benjamin Jenkins,Robert A Heaton,Iain P Hargreaves,Catherine E Aiken,Albert Koulman,Denise S Fernandez-Twinn

doi:10.1113/jp281902

Abstract

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg/kg/day) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669±568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass, and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (p<0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7±125.4 nmol/g in the placenta and 2063±2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk versus benefits that are weighed in obstetric medical treatments.

Highlights

The growing prevalence of obesity worldwide means that in many populations at least 50% of women are overweight or obese at the start of pregnancy (Hill et al 2019)
Exposure to a maternal high fat/high sugar diet resulted in a pronounced obesity phenotype and the subsequent development of glucose intolerance, insulin resistance and reduced uterine artery compliance during pregnancy
Metformin treatment in our model resulted in improvement of maternal metabolic and vascular parameters but did not improve placental or fetal parameters

Summary

Introduction

The growing prevalence of obesity worldwide means that in many populations at least 50% of women are overweight or obese at the start of pregnancy (Hill et al 2019). Maternal obesity and untreated GDM during pregnancy have direct effects on the fetus, with implications for long-term offspring health (Alfaradhi & Ozanne, 2011). Studies in animal models by our laboratory and others have shown previously that these relationships are causal. These studies demonstrate that obesity and/or glucose intolerance during pregnancy lead to cardiac dysfunction (Blackmore et al 2014), insulin resistance (Isganaitis et al 2014), hyperphagia (Steculorum & Bouret, 2011), obesity (Samuelsson et al 2008) and fatty liver (Alfaradhi et al 2014) in young adult offspring. The mechanisms linking fetal development and growth in affected pregnancies with long-term adverse effects are complex and yet to be fully understood

Methods

Results

Conclusion