Metformin use in pregnancy influence offspring brain development: Study

With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. It is an oral antidiabetic agent that can cross the placenta and can reach the fetus due to its relatively small molecular size and ability to pass through cell membranes. It may potentially alter neural development or influence mitochondrial function and cellular metabolism, processes that are critical for proper brain development.

For the study, researchers used two mouse models to represent the main causes of gestational diabetes: severe obesity of the mother before pregnancy and excessive weight gain during pregnancy. These metabolic states were achieved utilizing different feeding patterns, with the mice receiving either a high-fat or control diet. The antidiabetic treatment of female mice and their offspring took place during the lactation period as this corresponds to the third trimester of a human pregnancy in terms of brain development.

Treatment involved insulin, metformin, or a placebo, whereby the dosage was based on standard human treatments. The research team collected data on the body weight of the mice, analyzed various metabolic parameters and hormones, and examined molecular signalling pathways in the hypothalamus.

The results revealed that exposure to anti-diabetic treatment (metformin), in the context of maternal gestational weight gain, resulted in an increased body weight as compared to the control fed or the maternal obese condition. Furthermore, human studies of GDM-affected pregnancies showed that children exposed to metformin in utero are smaller at birth than those whose mothers were treated with insulin. However, metformin-exposed children do become heavier, with higher BMI, in childhood.

“As a result of antidiabetic treatment in the early postnatal period, we were able to identify alterations in the weight gain and hormonal status of the offspring, which were critically dependent on the metabolic state of the mother. Furthermore, sex-specific changes in hypothalamic AMPK signalling in response to metformin exposure were also observed. Together with the metformin-induced shift in the examined hormone levels, the results indicate that the maternal metabolic state must be taken into account before starting the treatment of gestational diabetes.” explained Dr. Rachel Lippert, Junior Research Group Leader.

Reference: Lídia Cantacorps, Jiajie Zhu, Selma Yagoub, Bethany M. Coull, Joanne Falck, Robert A. Chesters, Katrin Ritter, Miguel Serrano-Lope, Katharina Tscherepentschuk, Lea-Sophie Kasch, Maya Paterson, Paula Täger, David Baidoe-Ansah, Shuchita Pandey, Carla Igual-Gil, Annett Braune, Rachel N. Lippert; Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice; Journal: Molecular Metabolism; DOI: 10.1016/j.molmet.2023.101860