Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without previously diagnosed diabetes. GDM affects up to 10% of all pregnancies, imposing a significant adverse effect on the health of both mother and fetus. To date, the underlying mechanism of GDM remains elusive. Pregnancy is commonly associated with insulin resistance in the mother, a physiological response that serves to spare blood glucose supplies for the fetus. To overcome insulin resistance, pancreatic ?-cells of pregnant mothers release more insulin into the blood. Such an adaptive response, termed ??-cell compensation?, is essential for maintaining normal blood glucose metabolism in pregnancies. In at-risk pregnant women, ?-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. Nonetheless, how ?-cells compensate for maternal insulin resistance during pregnancy and what causes ?-cell failure in GDM are poorly understood. To decipher the mechanism of ?-cell compensation for pregnancy, we determined gestational regulation of ?-cell mass and function by FoxO1 - a key transcription factor that integrates insulin signaling and nutritional cues to cell metabolism, survival, proliferation and differentiation. We found that ?-cell FoxO1 expression is markedly upregulated, coinciding with the physiological induction of ?-cell compensation in mice during pregnancy. Furthermore, we showed that ?-cell FoxO1 deficiency predisposes pregnant female mice to GDM, as evidenced by the induction of impaired glucose tolerance, elevated blood glucose levels and reduced glucose-stimulated insulin secretion during pregnancy. These new data underscore the importance of FoxO1 in governing the adaptive changes of ?-cell mass and function in response to pregnancy, spurring the hypothesis that FoxO1 deregulation may be the missing link between maternal insulin resistance and ?-cell decompensation in GDM. To address this hypothesis, we will use rigorous in vivo and ex vivo studies to characterize the role of FoxO1 in integrating gestational hormonal signaling to adaptive changes in ?-cell mass and function during pregnancy. We will determine the mechanism by which FoxO1 augments ?-cell compensation for maternal insulin resistance in female mice. Furthermore, we will determine the mechanism of how ?-cell FoxO1 deficiency causes ?-cell decompensation, contributing to the development of GDM. Accomplishing this project will deepen our understanding of gestational ?-cell compensation for maternal insulin resistance, providing new mechanistic insights into ?-cell decompensation and GDM.
Gestational diabetes mellitus (GDM) is characterized by high blood sugar levels during pregnancy. About 1 out of 10 pregnant women develops GDM - a major complication that imposes a significant risk on the health of both mothers and babies. Our goal is to understand how pancreatic ?-cells compensate for pregnancy to gain mechanistic insights into ?-cell failure in GDM.