Abstract
Background While metformin is the first-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. In this study, we aimed to investigate the biodistribution of metformin in the pregnant chinchilla, a species exhibiting placental characteristics comparable with the pregnant woman. Furthermore, we aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy. Methods Three chinchillas in the last part of gestation were injected with [11C]-metformin and scanned by PET/CT for 70 minutes to visualize the distribution. To investigate the difference in expression of placenta transporters between humans and chinchillas, PCR was performed on samples from five chinchilla placentae and seven human placentae. Results Dynamic PET with [11C]-metformin showed that the metformin distribution in chinchillas was similar to that in nonpregnant humans, with signal from kidneys, liver, bladder, and submandibular glands. Conversely, no radioactive signal was observed from the fetuses, and no metformin was accumulated in the chinchilla fetus when measuring the SUV. PCR of placental mRNA showed that the human placentae expressed OCT3, whereas the chinchilla placentae expressed OCT1. Conclusion Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies.
Highlights
Today, 5% of all pregnant women develop gestational diabetes mellitus (GDM), and this prevalence is expected to increase due to the increasing proportion of overweight and obesity [1]
Prior to the positron emission tomography (PET) examination, intravenous access was gained through the tail vein and used for radiotracer injection. e animals were placed in the field of view in a PET-CT system (Siemens, Erlangen, Germany). 11C-metformin was prepared as previously described [15], containing metformin dissolved in aqueous (NH4)2HPO4 (100 mM, pH 5)
We found that human placentae express OCT3 whereas chinchillas express OCT1 (Figure 5). is difference in transporters could be the reason for the missing uptake of metformin in the chinchilla placenta and fetus
Summary
5% of all pregnant women develop gestational diabetes mellitus (GDM), and this prevalence is expected to increase due to the increasing proportion of overweight and obesity [1]. Metformin is rst-line pharmacological treatment of diabetes mellitus type 2 (DM2) [3] and polycystic ovary syndrome (PCOS). It has few side e ects, mainly gastrointestinal symptoms such as diarrhea and nausea [4], and is associated with a low risk of hypoglycemia and lactate acidosis [5]. While metformin is the rst-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. We aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy. Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies
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