Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α

  1. Samar I. Itani1,
  2. Neil B. Ruderman1,
  3. Frank Schmieder2 and
  4. Guenther Boden3
  1. 1Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, Massachusetts
  2. 2Department of Surgery and the General Clinical Research Center, Temple University Hospital, Philadelphia, Pennsylvania
  3. 3Division of Endocrinology, Diabetes, and Metabolism and the General Clinical Research Center, Temple University Hospital, Philadelphia, Pennsylvania

    Abstract

    The possibility that lipid-induced insulin resistance in human muscle is related to alterations in diacylglycerol (DAG)/protein kinase C (PKC) signaling was investigated in normal volunteers during euglycemic-hyperinsulinemic clamping in which plasma free fatty acid (FFA) levels were increased by a lipid/heparin infusion. In keeping with previous reports, rates of insulin-stimulated glucose disappearance (GRd) were normal after 2 h but were reduced by 43% (from 52.7 ± 8.2 to 30.0 ± 5.3 μmol · kg–1 · min–1, P < 0.05) after 6 h of lipid infusion. No changes in PKC activity or DAG mass were seen in muscle biopsy samples after 2 h of lipid infusion; however, at ∼6 h, PKC activity and DAG mass were increased approximately fourfold, as were the abundance of membrane-associated PKC-βII and -δ. A threefold increase in membrane-associated PKC-βII was also observed at ∼2 h but was not statistically significant (P = 0.058). Ceramide mass was not changed at either time point. To evaluate whether the fatty acid–induced insulin activation of PKC was associated with a change in the IkB kinase (IKK)/nuclear factor (NF)-κB pathway, we determined the abundance in muscle of IκB-α, an inhibitor of NF-κB that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IκB-α mass was observed after 2 h of lipid infusion, but at ∼6 h, IκB-α was diminished by 70%. In summary, the results indicated that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic-hyperinsulinemic clamping was associated with increases in DAG mass and membrane-associated PKC-βII and -δ and a decrease in IκB-α. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-β/IκB/NFκB pathway remains to be established.

    Footnotes

    • Address correspondence and reprint requests to Dr. Guenther Boden, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140. E-mail: bodengh{at}tuhs.temple.edu.

      Received for publication 6 March 2002 and accepted in revised form 6 May 2002. Posted on the World Wide Web at http://www.diabetes.org/diabetes/rapidpubs.shtml on 7 June 2002.

      DAG, diacylglycerol; FFA, free fatty acid; GRa, total body glucose appearance; GRd, total body glucose disappearance; IKK, IκB kinase; IMCL-TG, intramyocellular triglyceride; NF, neclear factor; NIH, National Institutes of Health; PI, phosphatidylinositol; PKC, protein kinase C.

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