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

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.

• Authors: Qin Zhang, Edward A Carter, Bang-Yi Ma, Morris White, Alan J Fischman, Ronald G Tompkins
• Journal: Life sciences (Life Sci) Vol. 77 Issue 24 Pg. 3068-77 (Oct 28 2005) ISSN: 0024-3205 [Print] Netherlands
• PMID: 15982669 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Phosphoproteins
• Proto-Oncogene Proteins
• 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

Topics

• Animals
• Burns (complications, metabolism)
• Disease Models, Animal
• Enzyme Activation
• Hindlimb (cytology, injuries, 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, injuries, 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