期刊
DIABETES
卷 51, 期 7, 页码 2005-2011出版社
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.51.7.2005
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资金
- NHLBI NIH HHS [HL 07224-25, P01 HL 55854] Funding Source: Medline
- NIA NIH HHS [R01 AG 07988] Funding Source: Medline
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-hypeirinsulinemic 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 mumol . 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 similar to6 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 similar to2 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, similar to6 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.
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