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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Horton, J. D. Ou, J. Brown, M. S. Bashmakov, Y. Zhang, J. Goldstein, J. L. |
| Description | Author Affiliation: Zhang J ( Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.); |
| Abstract | Recent data indicate that sustained elevations in plasma insulin suppress the mRNA for IRS-2, a component of the insulin signaling pathway in liver, and that this deficiency contributes to hepatic insulin resistance and inappropriate gluconeogenesis. Here, we use nuclear run-on assays to show that insulin inhibits transcription of the IRS-2 gene in the livers of intact rats. Insulin also inhibited transcription of a reporter gene driven by the human IRS-2 promoter that was transfected into freshly isolated rat hepatocytes. The human promoter contains a heptanucleotide sequence, TGTTTTG, that is identical to the insulin response element (IRE) identified previously in the promoters of insulin-repressed genes. Single base pair substitutions in this IRE decreased transcription of the IRS-2-driven reporter in the absence of insulin and abolished insulin-mediated repression. We conclude that insulin represses transcription of the IRS-2 gene by blocking the action of a positive factor that binds to the IRE. Sustained repression of IRS-2, as occurs in chronic hyperinsulinemia, contributes to hepatic insulin resistance and accelerates the development of the diabetic state. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 7 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Hepatocytes Drug Effects Insulin Pharmacology Phosphoproteins Genetics Animals Cells, Cultured Diabetes Mellitus, Type 2 Complications Genes, Reporter Physiology Hyperinsulinism Etiology Insulin Receptor Substrate Proteins Insulin Resistance Intracellular Signaling Peptides And Proteins Lipodystrophy Mice Molecular Sequence Data Promoter Regions, Genetic Rats, Sprague-Dawley Sequence Homology, Nucleic Acid Transcription, Genetic Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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