Research Project
10289571
SUMMARY During a normal pregnancy, maternal insulin sensitivity declines in the second and third trimester to allow glucose delivery to the fetus, while maternal beta cell mass and insulin secretion dramatically increase. In gestational diabetes (GDM), there is a mismatch between insulin resistance and demand, resulting in glucose intolerance. In some patients, particular those who are obese, excess insulin resistance drives this mismatch, whereas in other patients, particularly lean women, insulin deficiency is the main contributor. There is a need for research that addresses the distinct causes of GDM in these patients. The proposed project will utilize a mouse model caused by acute high fat feeding that resembles GDM in lean women; they are glucose intolerant only during pregnancy, insulin resistant, but with failed beta cell proliferation and reduced insulin secretion. Preliminary show that the diet specifically interferes with placentally-stimulated beta cell proliferation. Extensive placental histological data from women with GDM show that placental villous maturation and angiogenesis are disrupted at term. Furthermore, genes associated with angiogenesis in the placenta and with responsiveness to placental signals in the islet are disrupted near term in the mouse model. Together these findings suggest that placental function is disrupted in GDM, in ways that contribute to the effects on both maternal and infant health. Aim 1 of the proposed project is to profile paired placental-islet samples over the course of gestation in normal pregnancies, and those complicated by GDM in the mouse to identify disruptions to placenta-beta cell cross-communication. Aim 2 will examine placental angiogenesis in early pregnancy and at term in both the mouse model and, by using ultrasound, in women with GDM. Together, these studies will show whether alterations in the placenta precede the onset of glucose intolerance and potentially contribute to the pathophysiology of GDM.
