Abstract
Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.
Highlights
Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS1)-associated phosphatidylinositol 3-kinase (PI3-kinase)
Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)- activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser307 phosphorylation
The changes in these fatty acid metabolite concentrations were compared with changes in insulin-stimulated insulin receptor tyrosine phosphorylation, IRS-1 tyrosine phosphorylation, IRS-1-associated PI3-kinase activity, and PKC- translocation
Summary
Vol 277, No 52, Issue of December 27, pp. 50230 –50236, 2002 Printed in U.S.A. Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle*. More recent 31P/13C NMR studies in humans have revealed a very different mechanism of fatty acid-induced insulin resistance whereby an increase in plasma fatty acid concentration was shown to result in lower intramyocellullar glucose 6-phosphate (9, 14) and glucose concentrations (10), suggesting that fatty acids inhibit insulin-stimulated glucose transport activity (10) These changes were associated with reduced insulin-stimulated IRS-11 tyrosine phosphorylation (11) and IRS-1-associated phosphatidylinositol 3-kinase (PI3kinase) activity (10, 11) suggesting that fatty acids cause insulin resistance through inhibition of insulin signaling, which we hypothesized might occur through activation of a serine kinase cascade involving PKC- (11). To explore the possible roles of different intracellular fatty acid metabolites such as fatty acylCoA, diacylglycerol (DAG), ceramides, and triglycerides in mediating fatty acid-induced insulin resistance in skeletal muscle, we measured these metabolites at different time intervals during a lipid infusion in relation to insulin stimulation: (i) insulin receptor tyrosine phosphorylation, (ii) IRS-1 tyrosine phosphorylation, and (iii) IRS-1-associated PI3-kinase activity as well as PKC- translocation. In a separate group of in vitro soleus muscle studies, we examined whether fatty acid-induced defects in insulin signaling were coupled to defects in insulinstimulated glucose uptake across a range of insulin concentrations
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