Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes

J. Zhang, J. Ou, Y. Bashmakov, J. D. Horton, M. S. Brown, J. L. Goldstein

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3756-3761
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number7
DOIs
StatePublished - Mar 27 2001

Keywords

  • Gluconeogenesis
  • Insulin resistance
  • Phosphoeno/pyruvate carboxykinase
  • Type 2 diabetes

ASJC Scopus subject areas

  • General

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