The expression of chromosome 19 miRNA cluster members during insulin sensitivity changes in pregnancy

Hypothesis: Declines in insulin sensitivity during pregnancy important for fetal growth are associated with impairments in skeletal muscle post-receptor insulin signaling. The primary initiator of these changes is unknown but believed to originate in the placenta. We hypothesize that placental miRNA are associated with maternal sensitivity changes and impact insulin-sensitive mechanisms in target tissues in vitro. Methods: Using qPCR, miRNA expression was measured in plasma in early (12-16 wk) and late (34-36 wk) gestation and placental tissue at term (37- 41 weeks) collected from independent cohorts. Insulin-sensitive glucose uptake was measured in human skeletal muscle myoblasts exposed to miRNA mimics in vitro. Multi-linear and binomial regression models were generated to test for associations between miRNAs, insulin sensitivity and fetal growth outcomes, adjusting for relevant clinical variables. P<0.05 was considered significant. Results: Placental expression of chromosome 19 miRNA cluster (C19MC) members was higher in patients with obesity (P<0.001) and positively correlated with maternal HOMA-IR (miR-516b-5p, miR-517a-3p, miR-1283 P<0.03). Placental expression of miR-517a-3p was higher in offspring with high adiposity and birthweight. Plasma miR-517a-3p in early (R2=0.13, P=0.02) and late (R2=0.14, P=0.02) pregnancy was related to decreases in insulin sensitivity during pregnancy. Mimics for miR-517a-3p and miR-524-3p both impaired insulin-sensitive glucose uptake in human skeletal myocytes in vitro (P<0.05). Conclusions: Our findings based on data from two independent pregnancy cohorts and in vitro studies support a role for the C19 cluster of miRNA – particularly miR-517a-3p - in physiological changes in insulin sensitivity over pregnancy, which may impact fetal growth.