Article
- The EMBO Journal (2004) 23, 582 - 593
- doi:10.1038/sj.emboj.7600082
Published online: 29 January 2004
Subject Categories:
Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice
Gregory J Cooney1,a, Ruth J Lyons2,a, 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
- Diabetes and Obesity, Garvan Institute of Medical Research, Sydney, NSW, Australia
- Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
Correspondence to:
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
aThese authors contributed equally to this work
Received 15 May 2003; Accepted 23 December 2003
Abstract
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.
Keywords:
- Grb7 family,
- insulin receptor,
- metabolism,
- PKB,
- signal transduction
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