Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice

EMBO J. 2004 Feb 11;23(3):582-93. doi: 10.1038/sj.emboj.7600082. Epub 2004 Jan 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adipose Tissue / metabolism
  • Animals
  • Deoxyglucose / metabolism
  • Glucose / metabolism
  • Glycogen / metabolism
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Organ Specificity / genetics
  • Organ Specificity / physiology
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics*
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, Insulin / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Grb14 protein, mouse
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Glycogen
  • Deoxyglucose
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose