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 function (i.e., nutrient flux and placental inflammation) to the growing fetus, thereby programming the metabolic health of the offspring. In this supplemental award, we will test the main hypothesis that the increased body weight and glucose intolerance programming in the offspring by maternal hyperinsulinemia is caused in part by increased placental inflammation. To test that maternal hyperinsulinemia programs metabolic dysfunction in offspring by accelerating the proinflammatory phase of placental development during gestation, we will perform the following two specific aims: Aim1: Investigate whether maternal hyperinsulinemia, in the absence of hyperglycemia and obesity, is sufficient to alter immune cell composition and potentiate placental inflammation. Aim2: Examine the metabolic health trajectory of offspring born to dams with hyperinsulinemia to assess if placental inflammation can lead to the predisposition of metabolic diseases. These studies are highly significant because they will define the molecular mechanisms whereby maternal hyperinsulinemia impacts metabolic health, and they underscore the importance of clinically controlling insulin levels during pregnancy, like glucose, to improve pregnancy outcomes. Thus, the anticipated success of this project will have significant implications in improving women’s reproductive health and the metabolic health of the offspring.