Placental miRNAs paracrine and endocrine roles in insulin sensitivity in pregnancy

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Project Abstract The physiological decrease in maternal insulin sensitivity during pregnancy is necessary to increase nutrient availability for placental uptake and fetal delivery. When the decrease in insulin sensitivity is excessive, it results in adverse pregnancy outcomes such as gestational diabetes leading to fetal macrosomia and hypoglycemia at delivery, and long-term risk for development of diabetes in mother and offspring. The mechanisms regulating insulin signaling during pregnancy are unknown. Maternal insulin sensitivity improves 120% within hours following delivery of the placenta, suggesting a placental factor may regulate insulin signaling during pregnancy. We have identified microRNAs (miRNAs) produced in the placenta that are associated with maternal insulin sensitivity index in late pregnancy. We detected some of these placenta-expressed miRNAs in maternal circulation as early as 8-12 weeks of gestation, suggesting they may be involved in the physiological adaptations of maternal glucose metabolism beginning early in pregnancy. The overall goal of this study is to investigate mechanisms by which selected candidate placental miRNA participate in the interplay between placenta and glucose-insulin regulation during pregnancy. We hypothesize that miRNA produced in the placenta and regulated by maternal glycemia, act locally and peripherally to manipulate maternal insulin sensitivity during pregnancy. To test this hypothesis, we will leverage our existing perinatal cohorts which include longitudinal prospectively collected plasma samples and insulin sensitivity index (ISI) data derived from oral glucose tolerance tests in the first, second and third trimesters of pregnancy. We will also utilize in vitro human primary cellular models to directly test the function of placenta-derived miRNA locally (paracrine actions in placenta) and in insulin-sensitive peripheral tissues (endocrine actions). Upon completion of the proposed studies we will have determined: 1) the local effect of placental miRNA related to maternal insulin sensitivity on placental gene expression and function; 2) the peripheral effect of placental miRNA related to maternal insulin sensitivity on skeletal myocytes, adipocytes and hepatocytes in vitro; 3) the regulatory role of hyperglycemia on placental miRNA expression and release. A detailed understanding of the function and regulation of these placental miRNA may provide us with novel targets for treatment of pathophysiological decreases in insulin sensitivity.