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Mechanisms of muscle insulin resistance in obese individuals

G L Dohm1

  • 1Department of Biochemistry, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.

International Journal of Sport Nutrition and Exercise Metabolism
|March 28, 2002
PubMed

Insights

Obesity-linked insulin resistance may stem from protein kinase C (PKC) overactivity. Elevated PKC phosphorylates the insulin receptor, reducing its function and impairing glucose uptake in muscle tissue.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Metabolic Disorders

Background:

  • Insulin resistance in obesity is linked to impaired insulin signaling in skeletal muscle.
  • Previous work indicated reduced insulin receptor tyrosine kinase activity in obese individuals.

Purpose of the Study:

  • To review evidence supporting the role of protein kinase C (PKC) in causing insulin resistance.
  • To investigate the mechanism by which PKC affects insulin receptor activity.

Main Methods:

  • Analysis of data on insulin receptor phosphorylation and kinase activity.
  • Studies involving alkaline phosphatase treatment of insulin receptors.
  • Experiments with PKC inhibitors and activators on human muscle tissue.
  • Measurement of PKC isoform levels in muscle biopsies.

Main Results:

  • PKC phosphorylates the insulin receptor on serine/threonine residues, decreasing its tyrosine kinase activity.
  • Alkaline phosphatase treatment restored tyrosine kinase activity in insulin receptors from obese subjects.
  • PKC inhibition improved insulin action in obese muscle; PKC activation induced insulin resistance in lean muscle.
  • Elevated levels of the beta isoform of PKC were observed in obese, insulin-resistant individuals.

Conclusions:

  • Elevated PKC activity is a likely cause of insulin resistance in obese individuals.
  • PKC-mediated hyperphosphorylation of the insulin receptor impairs its function.
  • Targeting PKC may offer a therapeutic strategy for insulin resistance.

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