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Published online July 15, 2008
Diabetes 57:2595-2602, 2008
DOI: 10.2337/db08-0038
© 2008 by the American Diabetes Association
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Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

Sara M. Reyna1,2, Sangeeta Ghosh1,2, Puntip Tantiwong1,2, C.S. Reddy Meka1,2, Phyllis Eagan2, Christopher P. Jenkinson1, Eugenio Cersosimo1,2, Ralph A. DeFronzo1,2, Dawn K. Coletta1, Apiradee Sriwijitkamol1,2, and Nicolas Musi1,2,3

1 Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas
2 Texas Diabetes Institute, San Antonio, Texas
3 Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, Texas

Corresponding author: Nicolas Musi, nicolas.musi{at}uhs-sa.com

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 NF{kappa}B-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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Copyright © 2008 by the American Diabetes Association.