17beta-Estradiol transcriptionally represses human insulin receptor gene expression causing cellular insulin resistance

In this study, we demonstrate that 17beta-estradiol (E(2)) inhibits human insulin receptor (IR) gene expression in a dose- and time-dependent manner in U-937 human promonocytic cells. Using cells transfected with the -1819 to -271 bp fragment of the human IR promoter (wild type promoter) and treated with E(2), we show that this repression is regulated at the transcriptional level. The steroid was also found to diminish the insulin responsiveness of the cells in terms of cell survival, DNA synthesis, glucose transport, and glucose oxidation, this last effect possibly involving reduced phosphatidylinositol 3-kinase (PI3-kinase) activity. These data provide new information on the molecular mechanisms of estrogen-inducing insulin resistance in human cells.