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.
Original language | English |
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Pages (from-to) | 582-593 |
Number of pages | 12 |
Journal | The EMBO Journal |
Volume | 23 |
Issue number | 3 |
DOIs | |
Publication status | Published - 11 Feb 2004 |
Externally published | Yes |
Keywords
- Grb7 family
- Insulin receptor
- Metabolism
- PKB
- Signal transduction