ONLINE LETTER TO THE EDITOR
Comment on: Reyna et al. (2008) Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects. Diabetes 57:2595–2602 Haim Shapiro,1 Pierre Singer,2,3 and Joelle Attal-Singer3,4
W
e read with interest an important finding by Reyna et al. (1) that the toll-like receptor (TLR)43nuclear factor B (NFB) pathway is overstimulated in the skeletal muscle of patients with type 2 diabetes and that this may be secondary to free saturated fatty acid (FSFA) activation of TLR4. We would like the investigators’ opinion on how their data should be interpreted in light of previous data regarding interactions between diet, TLR4 signaling, and insulin sensitivity. Type 2 diabetic patients suffer from low-grade endotoxemia, possibly because of aberrant intestine-microflora interactions or impaired neutralization of lipopolysaccharide (LPS) (2,3). The ongoing activation of TLR4 may contribute to the chronic, low-grade inflammatory response and reduced insulin sensitivity that characterize this illness (2,3). Contrarily, exposure to LPS induces “endotoxin tolerance” (i.e., reduced signaling via TLR4 upon restimulation). The molecular underpinnings of this phenomenon are complex but include reduced TLR4 expression and increased levels of agents that antagonize downstream signal molecules (4,5). We are curious as to why, in the investigators’ opinion, a similar downregulation of TLR4 signaling does not appear to occur in the muscle of diabetic patients, which is exposed to fluctuating concentrations of LPS and FSFA. From the 1Institute for Nutrition Research, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel the 2Department of General Intensive Care, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; the 3Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and the 4Institute of Endocrinology, Diabetes Services, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel. Corresponding author: Haim Shapiro,
[email protected]. DOI: 10.2337/db09-0022 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details.
DIABETES, VOL. 58, APRIL 2009
A second question relates to the potential therapeutic approaches that target the described overactivation of TLR4. Based on in vitro studies, whereas FSFAs activate NFB in monocyte/macrophage cell lines, extracellular fish oil– derived n-3 polyunsaturated fatty acids (PUFAs) attenuate the NFB-dependent gene transcription induced by LPS or FSFAs (6). This effect of n-3 is mediated by TLR4 inhibition (6), although n-3 PUFAs also inhibit the intracellular cascade leading to NFB-mediated expression of inflammatory mediators (7). What are the investigators’ thoughts on the role of n-3 PUFAs in diabetic and insulinresistant states? ACKNOWLEDGMENTS
No potential conflicts of interest relevant to this article were reported. REFERENCES 1. Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, Cersosimo E, Defronzo RA, Coletta DK, Sriwijitkamol A, Musi N: Elevated toll-like receptor 4 expression and signaling in muscle from insulinresistant subjects. Diabetes 57:2595–2602, 2008 2. Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S: Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292:E740 –E747, 2007 3. Gubern C, Lo´pez-Bermejo A, Biarne´s J, Vendrell J, Ricart W, Ferna´ndezReal JM: Natural antibiotics and insulin sensitivity: the role of bactericidal/ permeability-increasing protein. Diabetes 55:216 –224, 2006 4. Cavaillon JM, Adib-Conquy M: Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care 10:233, 2006 5. Nomura F, Akashi S, Sakao Y, Sato S, Kawai T, Matsumoto M, Nakanishi K, Kimoto M, Miyake K, Takeda K, Akira S: Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J Immunol 164:3476 –3479, 2000 6. Lee JY, Hwang DH: The modulation of inflammatory gene expression by lipids: mediation through Toll-like receptors. Mol Cells 21:174 –185, 2006 7. Mishra A, Chaudhary A, Sethi S: Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol 24:1621–1627, 2004
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