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.
García-Arencibia
Moisés
M
Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University, 28040 Madrid, Spain.
Molero
Susana
S
Dávila
Norma
N
Carranza
M Carmen
MC
Calle
Consuelo
C
D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011972:Receptor, Insulin / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D004958:Estradiol; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D005947:Glucose