The worldwide increase in the incidence of diabetes, the increase in type 2 diabetes in women at reproductive ages, and the cross-generation of the intrauterine programming of type 2 diabetes are the bases for the growing interest in the use of experimental diabetic models in order to gain insight into the mechanisms of induction of developmental alterations in maternal diabetes.In this scenario, experimental models that present the most common features of diabetes in pregnancy are highly required. Several important aspects of human diabetic pregnancies such as the increased rates of spontaneous abortions, malformations, fetoplacental impairments, and offspring diseases in later life can be approached by using the appropriate animal models. The purpose of this review is to give a practical and critical guide into the most frequently used experimental models in diabetes and pregnancy, discuss their advantages and limitations, and describe the aspects of diabetes and pregnancy for which these models are thought to be adequate. This review provides a comprehensive view and an extensive analysis of the different models and phenotypes addressed in diabetic animals throughout pregnancy. The review includes an analysis of the surgical, chemical-induced, and genetic experimental models of diabetes and an evaluation of their use to analyze early pregnancy defects, induction of congenital malformations, placental and fetal alterations, and the intrauterine programming of metabolic diseases in the offspring’s later life.

What are the consequences of inhibiting mTOR, the mechanistic target of rapamycin (mTOR), and the peroxisome proliferator activated receptor gamma (PPARγ) and PPARδ pathways in the early post-implantation period on decidual function, embryo viability and feto-placental growth in the rat? mTOR inhibition from Days 7 to 9 of pregnancy in rats caused decidual PPARγ and PPARδ upregulation on Day 9 of pregnancy and resulted in embryo resorption by Day 14 of pregnancy. PPARγ and PPARδ inhibition differentially affected decidual mTOR signaling and levels of target proteins relevant to lipid histotrophic nutrition and led to reduced feto-placental weights on Day 14 of pregnancy. Although mTOR, PPARγ and PPARδ are nutrient sensors important during implantation, the role of these signaling pathways in decidual function and how they interact in the early post-implantation period are unknown. Perilipin 2 (PLIN2) and fatty acid binding protein 4 (FABP4), two adipogenic proteins involved in lipid histotrophic nutrition, are targets of mTOR and PPAR signaling pathways in a variety of tissues. Rapamycin (mTOR inhibitor, 0.75 mg/kg, sc), T0070907 (PPARγ inhibitor, 0.001 mg/kg, sc), GSK0660 (PPARδ inhibitor, 0.1 mg/kg, sc) or vehicle was injected daily to pregnant rats from Days 7 to 9 of pregnancy and the studies were performed on Day 9 of pregnancy (n = 7 per group) or Day 14 of pregnancy (n = 7 per group). On Day 9 of pregnancy, rat decidua were collected and prepared for western blot and immunohistochemical studies. On Day 14 of pregnancy, the resorption rate, number of viable fetuses, crown–rump length and placental and decidual weights were determined. Inhibition of mTOR in the early post-implantation period led to a reduction in FABP4 protein levels, an increase in PLIN2 levels and an upregulation of PPARγ and PPARδ in 9-day-pregnant rat decidua. Most embryos were viable on Day 9 of pregnancy but had resorbed by Day 14 of pregnancy. This denotes a key function of mTOR in the post-implantation period and suggests that activation of PPAR signaling was insufficient to compensate for impaired nutritional/survival signaling induced by mTOR inhibition. Inhibition of PPARγ signaling resulted in decreased decidual PLIN2 and FABP4 protein expression as well as in inhibition of decidual mTOR signaling in Day 9 of pregnancy. This treatment also reduced feto-placental growth on Day 14 of pregnancy, revealing the relevance of PPARγ signaling in sustaining post-implantation growth. Moreover, following inhibition of PPARδ, PLIN2 levels were decreased and mTOR complex 1 and 2 signaling was altered in decidua on Day 9 of pregnancy. On Day 14 of pregnancy, PPARδ inhibition caused reduced feto-placental weight, increased decidual weight and increased resorption rate, suggesting a key role of PPARδ in sustaining post-implantation development. Not applicable. This is an in vivo animal study and the relevance of the results for humans remains to be established. The early post-implantation period is a critical window of development and changes in the intrauterine environment may cause embryo resorption and lead to placental and fetal growth restriction. mTOR, PPARγ and PPARδ signaling are decidual nutrient sensors with extensive cross-talk that regulates adipogenic proteins involved in histotrophic nutrition and important for embryo viability and early placental and fetal development and growth. Funding was provided by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina (PICT 2014-411 and PICT 2015-0130), and by the International Cooperation (Grants CONICET-NIH-2014 and CONICET-NIH-2017) to A.J. and T.J. The authors have no conflicts of interest.