Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: role of IRS phosphorylation

Life Sci. 2005 Oct 28;77(24):3068-77. doi: 10.1016/j.lfs.2005.02.034. Epub 2005 Jun 27.

Abstract

Hyperglycemia, glucose intolerance and elevated insulin levels frequently occur in burned patients; however, the mechanism(s) for this insulin resistance has not been fully elucidated. One possible mechanism could involve alterations in the phosphorylation of serine 307 of the insulin receptor substrate-1 (IRS-1) via activation of stress kinase enzymes, including SAPK/JNK. In the present study we examined the time course of the effect of burn injury to mice on: levels of IRS-1 protein, phosphorylation of serine 307 of IRS-1, SAPK/JNK kinase levels and activity and Akt kinase activity in hind limb skeletal muscle. Burn injury produced a reduction in hind limb muscle mass 24 h after injury, and, which persisted for 168 h. At 24 h after injury, there was a dramatic ( approximately 9-fold) increase in phosphorylation of IRS-1 serine 307 followed by a more moderate elevation thereafter. Total IRS-1 protein was slightly elevated at 24 h after injury and decreased to levels below sham treated animals at the later times. Burn injury did not appear to change total SAPK/JNK protein content, however, enzyme activity was increased for 7 days after injury. Akt kinase activity was decreased in skeletal muscle following burn injury; providing a biochemical basis for burn-induced insulin resistance. These findings are consistent with the hypothesis that burn-induced insulin resistance may be related, at least in part, to alterations in the phosphorylation of key proteins in the insulin signaling cascade, including IRS-1, and that changes in stress kinases, such as SAPK/JNK produced by burn injury, may be responsible for these changes in phosphorylation.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Burns / complications*
  • Burns / metabolism
  • Disease Models, Animal*
  • Enzyme Activation*
  • Hindlimb / cytology
  • Hindlimb / injuries
  • Hindlimb / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 4
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / injuries
  • Muscle, Skeletal / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, Insulin / metabolism
  • Signal Transduction

Substances

  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases