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

Author information

Affiliations

  • 1. Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75390, USA.
      Authors
    • Shimomura I 1
    (1 author)

Molecular Cell, 01 Jul 2000, 6(1):77-86
https://doi.org/10.1016/s1097-2765(05)00010-9 PMID: 10949029 

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.

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Read article at publisher's site: https://doi.org/10.1016/s1097-2765(05)00010-9

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Funding 

Funders who supported this work.

NHLBI NIH HHS (1)