title: Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.
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 (G(Rd)) were normal after 2 h but were reduced by 43% (from 52.7 +/- 8.2 to 30.0 +/- 5.3 micromol. 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 approximately 6 h, PKC activity and DAG mass were increased approximately fourfold, as were the abundance of membrane-associated PKC-betaII and -delta. A threefold increase in membrane-associated PKC-betaII was also observed at approximately 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)-kappaB pathway, we determined the abundance in muscle of IkappaB-alpha, an inhibitor of NF-kappaB that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IkappaB-alpha mass was observed after 2 h of lipid infusion, but at approximately 6 h, IkappaB-alpha 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-betaII and -delta and a decrease in IkappaB-alpha. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-beta/IkappaB/NFkappaB pathway remains to be established.
authors.affiliation: Diabetes Unit, Section of Endocrinology, Department of Medicine, Boston University Medical Center, Boston, MA, USA.
authors.forename: Samar I
authors.initials: SI
authors.lastname: Itani
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.forename: Frank
authors.initials: F
authors.lastname: Schmieder
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D020672:I-kappa B Proteins; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D004075:Diglycerides; D005230:Fatty Acids, Nonesterified; D020672:I-kappa B Proteins; D007328:Insulin; D007527:Isoenzymes; D008055:Lipids; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose