Abstract
AimsThe antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice.MethodsMetformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig-1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR.ResultsMetformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD-phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig-1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice.ConclusionsThe present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy.
Highlights
Metformin is a biguanide class of antidiabetic agent and it is the most commonly prescribed oral drug for the treatment of patients with type 2 diabetes
We hypothesised that prenatal metformin exposure might have long-term effects and here we show results which suggest that prenatal metformin exposure has a major impact on the metabolic phenotype of the offspring
Mice were housed on a 12 h:12 h dark:light cycle and fed either a regular diet (RD) containing 69% carbohydrates, 22% protein and 9% fat resulting in 3.6 kcal/g (diet CRM(E), SDS, UK) or high fat diet (HFD) containing 20% carbohydrates, 20% protein and 60% fat resulting in 5.2 kcal/g ad libitum
Summary
Metformin is a biguanide class of antidiabetic agent and it is the most commonly prescribed oral drug for the treatment of patients with type 2 diabetes. The main pharmacological effect of metformin is decreased hepatic gluconeogenesis [1,2]. It has been shown to improve insulin sensitivity, lipid profile, endothelial function, and body weight control [2]. Metformin possesses a favourable spectrum of actions for the treatment of overweight, type 2 diabetes patients. Several studies have shown that metformin exerts its beneficial metabolic effects through AMP-activated protein kinase (AMPK) [3,4]. AMPK is a cellular energy regulator that activates ATP-producing metabolic pathways [5,6] and autophagy [7,8] to normalise the energy balance of the cells
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