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- Title
Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice.
- Authors
Cooney, Gregory J.; Lyons, Ruth J.; Crew, A. Jayne; Jensen, Thomas E.; Molero, Juan Carlos; Mitchell, Christopher J.; Biden, Trevor J.; Ormandy, Christopher J.; James, David E.; Daly, Roger J.
- Abstract
Gene targeting was used to characterize the physiological role of growth factor receptor-bound (Grb)14, an adaptertype signalling protein that associates with the insulin receptor (IR). Adult male Grbl4-/- 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, insulininduced 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 Grbl4 ablation was observed on insulin signalling in white adipose tissue. These findings demonstrate that Grbl4 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.
- Subjects
GLUCOSE; HOMEOSTASIS; INSULIN; GROWTH factors; CYTOKINES; PEPTIDES; LABORATORY rats
- Publication
EMBO Journal, 2004, Vol 23, Issue 3, p582
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7600082