Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice

Iichiro Shimomura, Morihiro Matsuda, Robert E Hammer, Yuriy Bashmakov, Michael S Brown, Joseph L Goldstein

Research output: Contribution to journalArticle

650 Scopus citations

Abstract

In mice with too little fat (lipodystrophy) or too much fat (ob/ob), leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance. In both disorders, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. Here we show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalMolecular cell
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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