Intergenerational effects of the antioxidant Idebenone on the placentas of rats with gestational diabetes mellitus.

Experimental models of maternal diabetes lead to the intrauterine programming of Gestational Diabetes Mellitus (GDM) in the offspring, together with an intrauterine proinflammatory environment, feto-placental metabolic alterations and fetal overgrowth. The aim of this work was to evaluate the effect of the mitochondrial antioxidant Idebenone given to F0 mild pregestational diabetic rats on the development of GDM in their F1 offspring and the intergenerational programming of a pro-oxidant/proinflammatory environment that affects the placentas of F2 fetuses. Control and mild pregestational diabetic female rats (F0) were mated with control males, and Idebenone or vehicle was administered to diabetic rats from day 1 of gestation to term. The F1 female offspring were mated with control males and maternal and fetal plasma samples were obtained for metabolic determinations at term. The F2 fetuses and placentas were weighed, and placental protein levels and peroxynitrite-induced damage (immunohistochemistry), mRNA levels (PCR), nitric oxide production (Griess reaction), and number of apoptotic cells (TUNEL) were evaluated. The F1 offspring of F0 diabetic rats (treated or not with Idebenone) developed GDM. The placentas of GDM rats showed a decrease in the mRNA levels of manganese superoxide dismutase and an increase in the production of nitric oxide, peroxynitrite-induced damage, and connective tissue growth factor levels, alterations that were prevented by the maternal Idebenone treatment in F0 rats. In conclusion, the maternal treatment with Idebenone in pregestational diabetic F0 rats ameliorates the pro-oxidant/proinflammatory environment that affects the placentas of F2 fetuses, although it does not prevent F1 rats from developing GDM.

A novel rat model of gestational diabetes induced by intrauterine programming is associated with alterations in placental signaling and fetal overgrowth.

A family history of diabetes predisposes to gestational diabetes mellitus (GDM). We hypothesized that female offspring of rats with pre-gestational diabetes will develop GDM, a pathology associated with fetal overgrowth and altered placental signaling. We found normal glycemia and insulinemia in the offspring from pre-gestational diabetic rats at three months of age. However, consistent with GDM, maternal hyperglycemia and hyperinsulinemia and increased fetal weight were evident when compared to controls. In this intrauterine programmed GDM model, the placentas showed alterations in mTOR pathway: unchanged phosphorylation of 4EBP-1 and PKCα despite reduced total expression of 4EBP-1 and PKCα, and increased phosphorylation of SGK1. GDM placentas also showed reduced expression of PPARα and PPARγ, and increased lipoperoxidation, nitric oxide production and peroxynitrite-induced damage. We conclude that exposure of maternal diabetes in utero programs GDM in the female offspring, leading to a GDM model associated with impaired placental signaling pathways, increased pro-oxidant/pro-inflammatory environment and fetal overgrowth.