2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Insulin-Like Growth Factor Binding Protein-1 Gene Expression and Counteracts the Negative Effect of Insulin

Recent epidemiological studies have revealed a possible cor-relation between exposure to high levels of dioxins or dioxin-like compounds and diabetes. Yet the interaction between insulin and dioxin actions remains elusive. We studied the regulation of insulin-like growth factor binding protein-1 (IGFBP-1), a protein involved in glucose homeostasis and whose expression is down-regulated by insulin. We showed that 2,3,7,8-tetrachorodibenzo-p-dioxin (TCDD) specifically in-duced IGFBP-1 mRNA in human hepatocytes and HepG2 hu-man hepatoma cells (2.5- and 8-fold, respectively). Cellular and secreted IGFBP-1 protein levels were also up-regulated. Trans-fection and reporter assays showed that the IGFBP-1 promoter was activated by TCDD and that this activation was dependent on the integrity of a proximal xenobiotic-responsive elemen