Metformin in Pregnancy: Mixed Outcomes for Developing Brain

Summary: A new study explored the effects of metformin, a common treatment for gestational diabetes, on offspring’s brain development in a mouse model. While metformin benefits pregnant mothers with gestational diabetes, its impact on the children’s brain development remains uncertain, with the study indicating no positive effects on the offspring.

The research reveals that metformin’s influence varies based on the mother’s metabolic state during pregnancy and highlights sex-specific changes in the offspring’s hypothalamic signaling. These findings underscore the complexity of prescribing metformin during pregnancy and the importance of considering the maternal metabolic condition before treatment.

Key Facts:

1. Complex Effects of Metformin: Metformin treatment during pregnancy shows no clear benefits for offspring’s brain development, emphasizing the need to evaluate its use carefully.
2. Mother’s Metabolic State Matters: The impact of metformin on offspring is significantly influenced by the mother’s metabolic health during pregnancy, suggesting tailored approaches to gestational diabetes treatment.
3. Sex-Specific Brain Signaling Changes: The study identifies sex-specific alterations in hypothalamic AMPK signaling in offspring exposed to metformin, pointing to nuanced differences in treatment response.

Source: DZD

With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. Although it is known that the oral antidiabetic agent can cross the placental barrier, the impacts on the brain development of the child are largely unknown.

An interdisciplinary research team from the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) have now been able to demonstrate in a mouse model that although metformin has positive effects in pregnant animals, it does not in the offspring.

The results were published in the specialist journal Molecular Metabolism.

Current figures show that around one in six pregnant women worldwide are affected by a special form of diabetes known as gestational diabetes. According to the Robert Koch Institute, 63,000 women in Germany were affected by the disease in 2021, and the trend is increasing.

These numbers are alarming because excessively high blood sugar levels during pregnancy are associated with negative consequences for mother and child. This increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Long-Term Effect of Metformin on Offspring is Unclear
For several years, the placenta-crossing oral antidiabetic agent metformin has been increasingly gaining importance as an alternative to insulin administration when lifestyle changes show no success during the treatment of gestational diabetes.

However, there are currently only a few studies on the long-term effects of metformin on the health of offspring. It is known that metformin has an impact on the AMPK signaling pathway, which regulates the networking of nerve cells during brain development.

The interdisciplinary team of DIfE researchers led by Junior Research Group Leader Dr. Rachel Lippert therefore grappled with two central questions: Is metformin treatment only beneficial for the mother or also the child? And does metformin treatment lead to long-term negative physiological changes in the offspring, especially in connection with the development of neuronal circuits in the hypothalamus, a critical region in the regulation of energy homeostasis?

Mouse Models Shed some Light
To answer the key questions, the 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 by means of 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 signaling pathways in the hypothalamus.

Maternal Metabolic State is Crucial
“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,” explains Lippert.

Furthermore, sex-specific changes in hypothalamic AMPK signaling 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.

Focusing on Prevention
According to Rachel Lippert, treatment of gestational diabetes in future could entail developing a medication that is available for all and does not cross the placenta.

“Given the increasing prevalence, education about gestational diabetes and preventive measures are of vital importance. If we can find a way to manage lifestyle and diet more proactively, we are in a better position to exploit the potential of gestational diabetes treatment,” says Lippert.

Background Information
Metformin is an orally taken antidiabetic agent that lowers blood sugar levels by inhibiting glucose production in the liver and increasing the insulin sensitivity of the cells. It is often prescribed as a first-line treatment for people with type 2 diabetes.

Metformin is either used alone or in combination with other oral antidiabetic drugs or insulin preparations. The European Medicines Agency approved metformin for treatment during pregnancy in March 2022.

Funding
This study was funded by the German Research Foundation (DFG) under the Excellence Strategy of the German federal and state governments (EXC-2049–390688087, NeuroCure, RNL) and by the German Center for Diabetes Research (DZD) (82DZD03D2Y and 82DZD03D03, RNL).

About this neuropharmacology and neurodevelopment research news

Author: Birgit Niesing
Source: DZD
Contact: Birgit Niesing – DZD
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice” by Rachel Lippert et al. Molecular Metabolism

Abstract

Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice

Objective

The incidence of gestational diabetes mellitus (GDM) and metabolic disorders during pregnancy are increasing globally. This has resulted in increased use of therapeutic interventions such as metformin to aid in glycemic control during pregnancy. Even though metformin can cross the placental barrier, its impact on offspring brain development remains poorly understood.

As metformin promotes AMPK signaling, which plays a key role in axonal growth during development, we hypothesized that it may have an impact on hypothalamic signaling and the formation of neuronal projections in the hypothalamus, the key regulator of energy homeostasis. We further hypothesized that this is dependent on the metabolic and nutritional status of the mother at the time of metformin intervention.

Using mouse models of maternal overnutrition, we aimed to assess the effects of metformin exposure on offspring physiology and hypothalamic neuronal circuits during key periods of development.

Methods

Female C57BL/6N mice received either a control diet or a high-fat diet (HFD) during pregnancy and lactation periods. A subset of dams was fed a HFD exclusively during the lactation. Anti-diabetic treatments were given during the first postnatal weeks. Body weights of male and female offspring were monitored daily until weaning.

Circulating metabolic factors and molecular changes in the hypothalamus were assessed at postnatal day 16 using ELISA and Western Blot, respectively. Hypothalamic innervation was assessed by immunostaining at postnatal days 16 and 21.

Results

We identified alterations in weight gain and circulating hormones in male and female offspring induced by anti-diabetic treatment during the early postnatal period, which were critically dependent on the maternal metabolic state.

Furthermore, hypothalamic agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neuronal innervation outcomes in response to anti-diabetic treatment were also modulated by maternal metabolic state. We also identified sex-specific changes in hypothalamic AMPK signaling in response to metformin exposure.

Conclusion

We demonstrate a unique interaction between anti-diabetic treatment and maternal metabolic state, resulting in sex-specific effects on offspring brain development and physiological outcomes.

Overall, based on our findings, no positive effect of metformin intervention was observed in the offspring, despite ameliorating effects on maternal metabolic outcomes. In fact, the metabolic state of the mother drives the most dramatic differences in offspring physiology and metformin had no rescuing effect.

Our results therefore highlight the need for a deeper understanding of how maternal metabolic state (excessive weight gain versus stable weight during GDM treatment) affects the developing offspring.

Further, these results emphasize that the interventions to treat alterations in maternal metabolism during pregnancy need to be reassessed from the perspective of the offspring physiology.