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

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 −1 day −1 ) 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 −1 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 vs. benefits that are weighed in obstetric medical treatments.

Developmental programming by maternal obesity: Lessons from animal models

“…Treatment with a clinically relevant dose of metformin during pregnancy improved maternal metabolic health and placental function in a mouse model of diet-induced obesity but did not rescue foetal growth restriction. 44 To date, few studies have published metabolic outcomes in adult offspring exposed prenatally to metformin, and with conflicting results. Salomäki et al provided metformin during chow-fed pregnancy and found that metformin introduced IUGR at E18.5.…”

Hypoxia ameliorates maternal diet‐induced insulin resistance during pregnancy while having a detrimental effect on the placenta

“…Mice treated with an AMPK activator at mid‐gestation and then exposed to hypoxia until term had increased uterine artery diameters, greater uterine artery blood flow and only half of the altitude‐associated reduction in fetal growth found in their hypoxia‐exposed, vehicle‐treated counterparts (Lane et al, 2020 ). Interestingly, treatment of dams with diet‐induced obesity 1 week before mating and throughout pregnancy with metformin, which mode of action is AMPK activation, improved maternal metabolic health and reduced uterine artery compliance but did not correct placental structure or fetal growth restriction (Hufnagel et al, 2021 ). Taken together, our data suggest that activation of the hypoxia response could be a means for reducing maternal IR but is incapable of supporting fetal growth and survival, which are probably highly dependent on other factors such as placental functions and blood flow.…”

The physiology of obesity: from mechanisms to medicine (M2M). Part one

“…Hufnagel et al . (2022) highlight the effect of metformin in a mouse model of maternal obesity – improved glucose tolerance and reduced maternal fat mass. However, it did not correct placental structure of fetal growth restriction, emphasising the potential for direct effects of metformin on the fetus.…”