Journal
DIABETES
Volume 57, Issue 10, Pages 2595-2602Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db08-0038
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Funding
- the American Diabetes Association
- the National Institutes of Health [AG030979, DK080157, DK24092, DK067690, HL086089]
- the UTHSCSA Executive Research Committee
- the South Texas Health Research Center
- a Nathan Shock Center Pilot
- the U.S Department of Veterans Affairs
- the American Heart Association
- Faculty of Medicine Siriraj Hospital Mahidol University of Thailand
- the Endocrine Fellows Foundation
- the Thai Ministry of Public Health [T32 HL007446]
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OBJECTIVE-Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of kappa B (I kappa B)/nuclear factor kappa B (NF kappa B). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (I kappa B/NF kappa B) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS-TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate I kappa B/NF kappa B via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS-Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower I kappa B alpha content, an indication of elevated I kappa B/NF kappa B signaling. The increase in TLR4 and NF kappa B signaling was accompanied by elevated expression of the NFKB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated I kappa B/NF kappa B, and blockade of TLR4 prevented the ability of palmitate to stimulate the I kappa B/NF kappa B pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NF kappa B. CONCLUSIONS-Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.
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