1 Unlocking metabolic fate: How placental insulin/IGF-1 and mTOR signaling shape offspring health

Abstract Both genetic and environmental factors contribute to the development of Type 2 diabetes (T2D). Hyperinsulinemia is frequently observed in pregnant women with prediabetes, obesity, or gestational diabetes, and their offspring are at increased risk of developing T2D. However, there is a lack of longitudinal studies examining the long-term metabolic outcomes in offspring of hyperinsulinemic mothers. Moreover, the mechanistic link between maternal ­hyperinsulinemia and the programming of metabolic disease in offspring remains poorly understood. The prevailing view is that insulin does not cross the placenta to regulate fetal growth directly. Nonetheless, maternal insulin can function as a growth factor and anabolic hormone by binding to insulin receptors (IR) and insulin-like growth factor 1 receptors (IGF1R) on the placenta. This interaction can drive key placental functions, including nutrient transport to the fetus. As a result, maternal insulin may indirectly alter fetal development by modifying placental nutrient delivery to fetal metabolic tissues, potentially causing permanent changes that predispose offspring to T2D in adulthood. This seminar will examine the metabolic phenotypes of offspring born to hyperinsulinemic murine dams. It will also highlight findings on metabolic outcomes in offspring from otherwise normal pregnancies where insulin or IGF1 receptors were selectively deleted in the placenta during gestation. Finally, evidence from genetic mouse models demonstrating that both loss- and gain-of-function alterations in placental mTOR signaling can significantly influence susceptibility to type 2 diabetes will be presented. These effects appear to be mediated through changes in placental nutrient transport and subsequent altered nutrient sensing by fetal pancreatic beta cells in the offspring. Collectively, these observations support the concept that insulin/mTOR signaling in the placenta integrates maternal metabolic signals with fetal nutrient exposure, ultimately programming the metabolic health of the offspring.