Beta-cell compensation is an adaptive mechanism by which beta-cells increase insulin secretion to overcome insulin resistance for maintaining euglycemia in obesity. Likewise, beta-cell compensation occurs during pregnancy, a physiological state that is characterized by increased insulin demand from the fetus. This effect, along with acquired insulin resistance in the mother, promotes beta-cell compensation for maintaining glucose homeostasis during gestation. Insufficient beta-cell compensation for maternal insulin resistance contributes to gestational diabetes. To understand the underlying mechanism of gestational diabetes, we determined the role of FoxO1 in regulating beta-cell mass and function in response to maternal insulin resistance. FoxO1 is a key transcription factor that mediates insulin action on cell metabolism, survival, proliferation, differentiation and oxidative stress. We found that beta-cell FoxO1 expression becomes markedly upregulated, coinciding with the induction of beta-cell compensation in pregnant mice. To gain mechanistic insight into FoxO1-mediated induction of gestational beta-cell compensation, we generated FoxO1-KO mice, in which FoxO1 is conditionally deleted in mature islets of adult mice using an inducible Pdx1-Cre-ERT system. We showed that prior to gestation, female FoxO1-KO mice exhibited normal blood glucose metabolism. However, at gestational day 14.5, pregnant FoxO1-KO mice exhibited fasting hyperglycemia and glucose intolerance. These effects were attributable to abnormal glucose-stimulated insulin secretion profiles in pregnant FoxO1-KO vs. control female mice. Using in vivo Brdu-labeling assay, we showed that FoxO1-deficient islets were associated with impaired abilities to mount a compensatory induction in beta-cell mass during pregnancy. Our data characterize FoxO1 as a pivotal factor for regulating the adaptive changes of beta-cell mass and function during pregnancy.
J. Yamauchi: None. T. Zhang: None. S. Lee: None. H. Dong: None.
National Institutes of Health
