Improvement of insulin sensitivity promotes extravillous trophoblast cell migration stimulated by insulin-like growth factor-I

Abstract

Insulin-like growth factor-I (IGF-I) has been shown to stimulate extravillous trophoblast (EVT) cell migration and invasion, and to play a crucial role in placental function, thereby, influencing placental development and fetal growth. Insufficient invasion of EVT cells into the uterine endometrium leads to pregnancy-related complications, including spontaneous abortion, fetal growth restriction (FGR), and pregnancy-induced hypertension (PIH). Insulin-resistant conditions such as polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) have also been associated with abortion and PIH. However, the effects of IGF-I on EVT cells under insulin-resistant conditions have not been elucidated yet. The current study was undertaken to analyze the effects of IGF-I under insulin-resistant conditions and to determine whether improvement in insulin sensitivity alters IGF signaling and cell migration in the EVT. Incubation with pioglitazone, an insulin sensitizer, increased peroxisome proliferator-activated receptor-γ (PPARγ) expression after 48 h. A 48-h pre-incubation with insulin reduced the phosphorylation and concentration of the insulin receptors, which were increased by insulin treatment. Long-term exposure to insulin reduced phosphorylation of the IGF-I receptor, insulin receptor substrate-1 (IRS-1), and Akt, and also reduced EVT cell migration. However, when the cells were incubated with pioglitazone in addition to insulin for 48 h, the phosphorylation of these proteins was restored. This combination partially reversed the inhibitory effect of insulin on EVT cell migration. These results suggest that abnormalities in pregnancy that are induced by loss of insulin sensitivity can be treated by improving insulin sensitivity.