Modified Project Summary/Abstract Section Both genetic and environmental factors contribute to the development of Type 2 diabetes (T2D). Hyperinsulinemia is commonly seen among pregnant women with prediabetes, obesity, and gestational diabetes, and their offspring has a greater risk for developing T2D. Yet, no current study addresses the long-term/longitudinal metabolic outcomes of the offspring when the mother is hyperinsulinemic. Furthermore, the mechanistic link between maternal hyperinsulinemia and the programming of metabolic disease in the offspring remains largely unknown. The dogma is that insulin does not cross the placenta into the fetus to regulate fetal growth. However, maternal insulin can act as a growth factor and an anabolic hormone binding to the placental insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) to drive critical placental function, including nutrient flux to the fetus. Thus, maternal insulin can change placental function by altering nutrient availability to fetal metabolic tissues causing permanent changes that predispose the offspring to T2D in adulthood. Indeed, we have compelling preliminary data showing increased body weight and glucose intolerance in the offspring of hyperinsulinemic dams. We identified that placental-specific IR deletion has a beneficial effect in improving glucose tolerance in the offspring of hyperinsulinemic dams. These observations provide a strong premise that the placenta integrates maternal hyperinsulinemia signals with placental nutrient flux to the growing fetus, thereby programming the metabolic health of the offspring. In this grant, we will test the main hypothesis that the increased body weight and glucose intolerance programming in the offspring by maternal hyperinsulinemia is caused by increased placental nutrient flux to the fetus, which is mediated by increased IR and IGF1R signaling and their downstream targets, mTOR and GLUT4, in the placenta. To test this hypothesis, we dev