Pancreatic islet hepatocyte growth factor and vascular endothelial growth factor A signaling in growth restricted fetuses

• Severely growth restricted fetuses have impaired insulin secretion, islet size, and islet vascularity.
• These features of growth restricted fetuses may underlie their increased risk for developing type 2 diabetes as adults.
• Islet HGF and VEGFA signaling represent a potential mechanism linking islet growth and vascularity.
• Decreased pancreatic islet HGF and VEGFA are potentially responsible for impaired islet defects in IUGR.

Placental insufficiency leads to intrauterine growth restriction (IUGR) and a lifelong risk of developing type 2 diabetes. Impaired islet development in the growth restricted fetus, including decreased β-cell replication, mass, and insulin secretion, is strongly implicated in the pathogenesis of later life type 2 diabetes. Currently, standard medical management of a woman with a pregnancy complicated by placental insufficiency and fetal IUGR is increased fetal surveillance and indicated preterm delivery. This leads to the dual complications of IUGR and preterm birth – both of which may increase the lifelong risk for type 2 diabetes. In order to develop therapeutic interventions in IUGR pregnancies complicated by placental insufficiency and decrease the risk of later development of type 2 diabetes in the offspring, the mechanisms responsible for impaired islet development in these cases must be determined. This review focuses on current investigations testing the hypothesis that decreased nutrient supply to the IUGR fetus inhibits an intra-islet hepatocyte growth factor – vascular endothelial growth factor A (HGF – VEGFA) feed forward signaling pathway and that this is responsible for developmental islet defects.