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Diabetes 51:2005-2011, 2002
© 2002 by the American Diabetes Association, Inc.
Rapid Publication |
Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and I
B-
1 Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, Massachusetts
2 Department of Surgery and the General Clinical Research Center, Temple University Hospital, Philadelphia, Pennsylvania
3 Division of Endocrinology, Diabetes, and Metabolism and the General Clinical Research Center, Temple University Hospital, Philadelphia, Pennsylvania
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-ßII and -
. A threefold increase in membrane-associated PKC-ßII 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)-
B pathway, we determined the abundance in muscle of IB-
, an inhibitor of NF-B that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IB- mass was observed after 2 h of lipid infusion, but at 6 h, IB- 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-ßII and - and a decrease in IB-. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-ß/IB/NFB pathway remains to be established.
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