Long-term Denervation Impairs Insulin Receptor substrate-1-mediated Insulin Signaling in Skeletal Muscle

Metabolism. 2001 Feb;50(2):216-22. doi: 10.1053/meta.2001.20169.


Long-term denervation is associated with insulin resistance. To investigate the molecular bases of insulin resistance, the downstream signaling molecules of insulin receptor including insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI 3-K) were examined in skeletal muscle of rats after 7 days of denervation. Long-term denervation attenuated insulin-stimulated activation of the initial steps of the intracellular signaling pathway. Insulin-stimulated tyrosine phosphorylation of insulin receptor was reduced to 36% (P < .005), as was the phosphorylation of IRS-1 to 34% (P < .0001) of control. While insulin receptor protein level was unchanged, the protein expression of IRS-1 was significantly decreased in denervated muscles. Insulin-stimulated percent tyrosine phosphorylation of IRS-1, normalized to the IRS-1 protein expression, was also reduced to 55% (P < .01) of control in denervated muscle. Denervation caused a decline in the insulin-induced binding of p85 regulatory subunit of PI 3-K to IRS-1 to 61% (P < .001) and IRS-1-associated PI 3-K activity to 57% (P < .01). These results provide evidence that long-term denervation results in insulin resistance because of derangements at multiple points, including tyrosine phosphorylation of insulin receptor and its downstream signaling molecule, IRS-1, protein expression of IRS-1, and activation of PI 3-K.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Denervation / adverse effects*
  • Denervation / methods
  • Enzyme Activation / drug effects
  • Hindlimb
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • Male
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / innervation*
  • Muscle, Skeletal / metabolism
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding / drug effects
  • Protein Subunits
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects*
  • Time Factors


  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Phosphoproteins
  • Protein Subunits
  • Phosphotyrosine
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin