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Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action

Nature Medicine volume 11, pages 567–571 (2005)Cite this article

Abstract

Insulin receptor substrate-1 (IRS-1) and IRS-2 are known to transduce and amplify signals emanating from the insulin receptor1,2,3. Here we show that Grb2-associated binder 1 (Gab1), despite its structural similarity to IRS proteins4, is a negative modulator of hepatic insulin action. Liver-specific Gab1 knockout (LGKO) mice showed enhanced hepatic insulin sensitivity with reduced glycemia and improved glucose tolerance. In LGKO liver, basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 was elevated, accompanied by enhanced Akt/PKB activation. Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation. Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin-elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver.

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Figure 1: Generation of liver-specific Gab1 knockout mice.
Figure 2: Metabolic changes of LGKO mice.
Figure 3: In vivo insulin sensitivity.
Figure 4: Biochemical analysis of insulin signaling in LGKO mice.

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Acknowledgements

We thank R. Premont for triple-loxP constructs, M. White for antibodies to IRS-1 and IRS-2, R. Abraham for providing the lactate kit, and colleagues for discussion. This work was supported by US National Institutes of Health grants DK60484 to A.L.H., DK33651 to J.M.O. and GM53660 to G.S.F. G.S.F. was a recipient of a career development award from the American Diabetes Association.

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Authors and Affiliations

  1. Signal Transduction Program, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    Emilie A Bard-Chapeau, Shinong Long, Eric E Zhang & Gen-Sheng Feng

  2. Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Andrea L Hevener & Jerrold M Olefsky

  3. Department of Pathology, Molecular Pathology Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Eric E Zhang & Gen-Sheng Feng

Authors
  1. Emilie A Bard-Chapeau
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  2. Andrea L Hevener
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Correspondence to Gen-Sheng Feng.

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Supplementary information

Supplementary Fig. 1

Insulin-induced tyrosine phosphorylation of IRβ in LGKO liver. (PDF 57 kb)

Supplementary Fig. 2

Normal expression levels of proteins involved in insulin signalling. (PDF 48 kb)

Supplementary Fig. 3

Deletion of Gab1 leads to enhanced insulin signalling through IRS-1, -2 in hepatocytes. (PDF 49 kb)

Supplementary Table 1

Characteristics of mutant mice at 2 and 12 months of age (PDF 20 kb)

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Bard-Chapeau, E., Hevener, A., Long, S. et al. Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Nat Med 11, 567–571 (2005). https://doi.org/10.1038/nm1227

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