Metformin during pregnancy affects the brain development in offspring mice

With the rising incidence in gestational diabetes and metabolic disorders during pregnancy, the prescription of metformin is also increasing. Although it is known that the oral antidiabetic drug can cross the placental barrier, the effects on the child's brain development are largely unknown. An interdisciplinary team of researchers from the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) has now been able to show in a mouse model that metformin has positive effects on pregnant animals, but it does not benefit the offspring. The results were published in the journal Molecular Metabolism.

Recent figures show that globally, about one in six pregnant women are affected by a specific form of diabetes called gestational diabetes. As reported by the Robert Koch Institute, in Germany there were already 63,000 affected women in 2021, and the trend is increasing. These statistics are alarming because high blood sugar levels during pregnancy are associated with negative consequences for mother and child. Affected women face an increased risk of developing type 2 diabetes later on, while their children are at higher risk of metabolic disorders and obesity.

Long-term effect of metformin on offspring is unclear

For several years now, the placenta-permeable oral antidiabetic drug metformin has been increasingly recognized as an alternative to insulin therapy when lifestyle modifications fail in managing gestational diabetes. Yet, there is limited research on the long-term impacts of metformin on offspring health. It is known that metformin acts on the AMPK signaling pathway, which controls the networking of nerve cells during brain development.

^{Preparation of mouse brain slices for further imaging. The slices are attached to a glass slide using a brush. (photo: David Ausserhofer/DIfE)}

The interdisciplinary DIfE research team led by junior research group leader Dr. Rachel Lippert therefore addressed two central questions: Does Metformin treatment benefit solely the mother or extend its efficacy to the child? And does treatment with metformin lead to long-term negative physiological changes in the offspring, particularly in connection with the development of the neuronal circuits in the hypothalamus, a critical region for the regulation of energy balance?

Mouse models to shed light on the dark

To answer the key questions, the researchers used two mouse models that represent the main causes of gestational diabetes: severe maternal obesity before pregnancy and excessive weight gain during pregnancy. These metabolic states were achieved by different feeding patterns in which the mice were fed a high-fat diet or a control diet. The antidiabetic treatment of the female mice and their offspring was carried out during lactation, as this corresponds to the third trimester of human pregnancy in terms of brain development.

The therapy was based on insulin, metformin or a placebo, whereby the dosage was adapted to standard human therapies. The research team collected data on the body weight of the mice, analyzed various metabolic parameters and hormones, and investigated molecular signaling pathways in the hypothalamus.

Maternal metabolic state is crucial

"As a result of antidiabetic treatment in the early postnatal phase, we were able to identify changes in the weight gain and hormonal status of the offspring that were crucially dependent on the metabolic state of the mother," explains Lippert. In addition, sex-specific changes in hypothalamic AMPK signaling were found in response to metformin exposure. Together with the metformin-induced shift in the hormone levels examined, the results indicate that the maternal metabolic status must be taken into account before starting treatment for gestational diabetes.

Focusing on prevention

According to Rachel Lippert, future therapy for gestational diabetes may involve developing a medication that is accessible to all and does not cross the placenta. "Given the increasing prevalence, education about gestational diabetes and preventative measures are crucial. If we can find a way to make lifestyle and diet more proactive, we can better exploit the potential for treating gestational diabetes," says Lippert.

Originalpublication:

Cantacorps, L., Zhu, J., Yagoub, S., Coull, B M., Falck, J.,Chesters, R. A., Ritter, K., Serrano-Lope; M., Tscherepentschuk; K., Kasch, L.-S., Paterson, M., Täger, P., Baidoe-Ansah, D., Pandey, S., Igual-Gil, C.; Braune, A., Lippert, R. N.: Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice. Mol. Metab. 79:101860 (2023). [Open Access]

Source: Press Release DifE

Contact:
Dr. Rachel Lippert
NeuroCure
Head of the Junior Research Group Neurocircuit Development and Function
phone: +49(0)33200 88 - 2470
Email: rachel.lippert@dife.de