One of the major mechanisms by which
insulin modulates
glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of
transcription factors that are required for
insulin-regulated gene expression may contribute to
insulin resistance. We recently identified
insulin response element-binding protein-1 (IRE-BP1) as a
transcription factor that binds and transactivates multiple
insulin-responsive genes, but the regulation of
IRE-BP1 in vivo is largely unknown. In this study, we show that
IRE-BP1 interacts with the
insulin response sequence of the
IGF-I,
IGFBP-1, and
IGFBP-3 genes using
chromatin immunoprecipitation assay. Furthermore, activation by
IRE-BP1 is sequence specific and mimics that of the
insulin effect on gene transcription. Tissue expression of
IRE-BP1 is 50- to 200-fold higher in classical
insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver,
IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of
insulin-mediated phosphatidylinositol-3
kinase signaling. Therefore, in diabetes and
obesity, the mechanisms involved in reducing the transactivation of the
insulin response sequence by
IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent
DNA binding. Our study supports the notion that
IRE-BP1 may be relevant to the action of
insulin in vivo and may play a role in the development of
insulin resistance and diabetes.