The number of women who develop gestational diabetes during pregnancy has been increasing for years. Drugs used to treat diabetes, such as metformin, cross the placental barrier. In the specialist journal Molecular Metabolism, researchers report on a study with mice, in which metformin had an impact on offspring brain development—how exactly was dependent on the metabolic state of the mother.
The hypothalamus region of the brain plays a key role in regulating energy homeostasis. In mice, neuronal connectivity in the hypothalamus is established during the first postnatal weeks. This is a critical time window, during which antidiabetic treatment could lead to changes. For example, the diabetes drug metformin has an impact on the AMPK enzyme, which regulates axonal growth during brain development.
High-Fat or Control Diet
Researchers from the German Institute of Nutritional Research Potsdam-Rehbrücke (DIfE), Nuthetal, the German Center for Diabetes Research (DZD), Munich/Neuherberg, and the Charité- Universitätsmedizin Berlin investigated how metformin treatment and the metabolic state of the mother impact the physiology and brain development of young animals.
For the study, female mice received either a control diet or a high-fat diet before mating and during pregnancy and lactation periods. Obesity and excessive weight gain during pregnancy are the main risk factors for gestational diabetes. The mice that were fed a high-fat diet developed symptoms of a metabolic disorder and were hyperglycemic at the end of the lactation period.
Metformin During the Brain Development Period
During the first three postnatal weeks, both the mothers and offspring received metformin. Gestational diabetes is usually diagnosed between the 24th and 28th week of pregnancy and medical treatment is provided during the third trimester. With regard to brain development, the lactation period in rodents corresponds to the third trimester of a human pregnancy.
Metformin treatment had measurable but variable impacts on the weight and hormones of the offspring. The researchers also observed effects on various components of the AMPK signaling cascade in the developing hypothalamus of the young mice. These were influenced by the metformin treatment as well as the diet given to the mother and the sex of the offspring.
The scientists explain that early changes in the hypothalamus could predispose the offspring to metabolic disorders later in life. In future studies, the young animals could be observed until adulthood in order to better understand the long-term effects of metformin treatment.
Original publication:
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. Molecular Metabolism 2023 Dec 23; doi: 10.1016/j.molmet.2023.101860.