SIMPOSIO. Maternal diabetes: mechanisms involved in intrauterine programming of metabolic, cardiac and reproductive anomalies

JAWERBAUM A

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

Maternal diabetes increases the risks for embryo resorption and malformations, feto-placental impairments and perinatal morbidities. Besides, the offspring have increased risks of metabolic and cardiovascular diseases in their adult life, as a result of an adverse process of intrauterine programming that is still poorly understood. Animal models of diabetes and pregnancy are valuable tools to improve the understanding of the mechanisms of induction of these alterations. In our laboratory, using a model of mild pregestational diabetes, we found that diabetic rats mated with control males lead to offspring that have increased markers of a pro-oxidant/pro-inflammatory state in their hearts from the neonatal stage. In the offspring from these diabetic rats, increases in circulating lipid concentrations are evident from day 21 of age and increased circulating glucose concentrations are evident from the fifth month of age. Moreover, if normoglycemic three month-old offspring of pregestational diabetic rats are mated with control males, the pregnant rats develop gestational diabetes (GDM). At term, GDM fetuses are overweight and GDM placentas show reduced peroxisome proliferator activated receptors (PPARs) and increased mechanistic target of rapamycin (mTOR) signaling. PPARs and mTOR are nutritional regulators respectively activated by unsaturated fatty acids and amino acids, and respectively involved in anti-inflammatory and growth pathways. We found that PPARs can be activated in fetuses and placentas by supplementation of the maternal diet with oils rich in unsaturated fatty acids. Moreover, we found that these diets also have benefits in the offspring, as shown by reduced oxidative/inflammatory markers and reduced lipid content and peroxidation in the heart of the offspring of pregestational diabetic animals. These effects were similar to those found with the maternal administration of mitochondrial antioxidants, highlighting the relevance of oxidative stress in the intrauterine programming of offspring diseases in maternal diabetes. Besides, diets enriched in PUFAs in the pregnancy of pregestational diabetic animals (F0 generation) regulate placental PPAR and mTOR signaling, reduce feto-placental pro-oxidant/pro-inflammatory markers and prevent fetal overgrowth in the offspring that develop GDM during their pregnancy (F1). Our results suggest that impaired PPAR pathways are involved in the intrauterine programming of alterations in the heart, lipid metabolism, placental signaling and fetal growth in the offspring of pregestational diabetic rats, and that maternal supplements with oils enriched in PPAR ligands, possibly reducing the pro-oxidant/pro-inflammatory intrauterine environment, can prevent these alterations.