We read with interest an important finding by Reyna et al. (1) that the toll-like receptor (TLR)4→nuclear factor κB (NFκB) 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.

A second question relates to the potential therapeutic approaches that target the described overactivation of TLR4. Based on in vitro studies, whereas FSFAs activate NFκB in monocyte/macrophage cell lines, extracellular fish oil–derived n-3 polyunsaturated fatty acids (PUFAs) attenuate the NFκB-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 NFκB-mediated expression of inflammatory mediators (7). What are the investigators' thoughts on the role of n-3 PUFAs in diabetic and insulin-resistant states?

No potential conflicts of interest relevant to this article were reported.

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