Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle*

By Chunli Yu, Yan Chen, G. Cline, Dongyan Zhang, Haihong Zong, Yanlin Wang, R. Bergeron, Jason K. Kim, S. Cushman, G. Cooney and 4 more. Journal of Biological Chemistry, 2002

1,636 citations recorded by the source corpus.

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 ∼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)-θ 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. 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-θ leading to increased IRS-1 Ser307 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.

Subfields: Biochemistry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2f567b9ee2addfe214bac80c88dc4e0d5aba3f56

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Citations in the corpus

Role of bile acids and bile acid receptors in metabolic regulation. (2009, background): “Furthermore, the level of insulin receptor substrate-1 (IRS-1) serine-307 phosphorylation, which is linked to fatty acid-induced insulin resistance (356), is increased in skeletal muscle of FXR / mice (186).”
Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links (2012, neutral): “The development of insulin resistance with intralipid infusion is associated with an increase in muscle diacylglycerol content but independent of changes in ceramide and triglyceride content (Yu et al., 2002).”
Pathogenesis of Insulin Resistance in Skeletal Muscle (2010, background): “In response to physiologic euglycemic hyperinsulinemia of 2 to 4 hours’ duration, HK-II cytosolic activity, protein content, and mRNA levels increase by 50% to 200% in healthy nondiabetic subjects, and this is associated with the translocation of hexokinase II from the cytosol to the mitochondria.”
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Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. (2003, background): “Subsequent studies revealed that besides inhibiting glucose oxidation, FFA also inhibits insulin signaling [30,31] and glycogen synthesis in muscle [32,60–62], and promotes hepatic glucose production [63,64] and VLDL secretion [34,65–67].”
The nuts and bolts of AGC protein kinases (2010, background): “In addition, free fatty acids have been suggested to stimulate the activity of novel PKC isoforms, leading to IRS1 phosphorylatio”
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