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| Subject Categories: Signal Transduction | Molecular Biology of Disease |
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| The EMBO Journal
(2004) 23, 582–593, doi:10.1038/sj.emboj.7600082 Published online 29 January 2004 |
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| Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice |
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| Gregory J Cooney1, 3, Ruth J Lyons2, 3, A Jayne Crew2, Thomas E Jensen1, Juan Carlos Molero1, Christopher J Mitchell1, Trevor J Biden1, Christopher J Ormandy2, David E James1 and Roger J Daly2 |
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1 Diabetes and Obesity, Garvan Institute of Medical Research, Sydney, NSW, Australia 2 Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia To whom correspondence should be addressed Roger J Daly, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia. Tel: 61 2 92 95 8333; Fax: 61 2 92 95 8321; E-mail: r.daly@garvan.org.au 3 These authors contributed equally to this work Received 15 May 2003; Accepted 23 December 2003; Published online 29 January 2004. |
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| Abstract |
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| Gene targeting was used to characterize the physiological role of growth factor receptor-bound (Grb)14, an adapter-type signalling protein that associates with the insulin receptor (IR). Adult male Grb14-/- mice displayed improved glucose tolerance, lower circulating insulin levels, and increased incorporation of glucose into glycogen in the liver and skeletal muscle. In ex vivo studies, insulin-induced 2-deoxyglucose uptake was enhanced in soleus muscle, but not in epididymal adipose tissue. These metabolic effects correlated with tissue-specific alterations in insulin signalling. In the liver, despite lower IR autophosphorylation, enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and activation of protein kinase B (PKB) was observed. In skeletal muscle, IR tyrosine phosphorylation was normal, but signalling via IRS-1 and PKB was increased. Finally, no effect of Grb14 ablation was observed on insulin signalling in white adipose tissue. These findings demonstrate that Grb14 functions in vivo as a tissue-specific modulator of insulin action, most likely via repression of IR-mediated IRS-1 tyrosine phosphorylation, and highlight this protein as a potential target for therapeutic intervention. |
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| Keywords: Grb7 family, insulin receptor, metabolism, PKB, signal transduction |
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