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      Increased Toll-Like Receptor (TLR) Activation and TLR Ligands in Recently Diagnosed Type 2 Diabetic Subjects

      research-article
      Author(s): , PHD 1 , , PHD 1 , , BS 1 , , MD, PHD 1 , 2
      Publication date (Electronic):
      Journal: Diabetes Care
      Publisher: American Diabetes Association

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          Abstract

          OBJECTIVE

          Individuals with type 2 diabetes have a myriad of metabolic aberrations including increased inflammation, increasing their cardiovascular risk. Toll-like receptors (TLRs) and their ligands play a key role in insulin resistance and atherosclerosis. However, there is a paucity of data examining the expression and activity of TLRs in type 2 diabetes. Thus, in the present study, we examined TLR2 and TLR4 mRNA and protein expression, their ligands, and signaling in monocytes of recently diagnosed type 2 diabetic patients.

          RESEARCH DESIGN AND METHODS

          TLR mRNA, protein expression, TLR ligands, and TLR signaling were measured in freshly isolated monocytes from healthy human control subjects ( n = 23) and type 2 diabetic subjects ( n = 23) using real-time RT-PCR, Western blot, and flow cytometric assays.

          RESULTS

          Type 2 diabetic subjects had significantly increased TLR2, TLR4 mRNA, and protein in monocytes compared with control subjects ( P < 0.05). Increased TLR2 and TLR4 expression correlated with BMI, homeostasis model assessment–insulin resistance (HOMA-IR), glucose, A1C, N ε-(carboxymethyl) lysine (CML), and free fatty acid (FFA). Ligands of TLR2 and TLR4, namely, HSP60, HSP70, HMGB1, endotoxin, and hyaluronan levels, were elevated in type 2 diabetic subjects and positively correlated with TLR2 and TLR4. Type 2 diabetic subjects showed increased MyD88, phosphorylated IRAK-1, Trif, TICAM-1, IRF-3, and NF-κB p65 expression in monocytes compared with control subjects. Furthermore, TLR-MyD88-NF-κB signaling resulted in elevated levels of cytokines ( P < 0.05), but increased interleukin (IL)-1β, interferon (IFN)-γ, and endotoxin were not significant when adjusted for BMI.

          CONCLUSIONS

          In this comprehensive study, we make the novel observation that TLR2 and TLR4 expression and their ligands, signaling, and functional activation are increased in recently diagnosed type 2 diabetes and contribute to the proinflammatory state.

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          High Glucose Induces Toll-Like Receptor Expression in Human Monocytes

          Mohan R. Dasu, Sridevi Devaraj, Ling Zhao … (2008)
          OBJECTIVE—Hyperglycemia-induced inflammation is central in diabetes complications, and monocytes are important in orchestrating these effects. Toll-like receptors (TLRs) play a key role in innate immune responses and inflammation. However, there is a paucity of data examining the expression and activity of TLRs in hyperglycemic conditions. Thus, in the present study, we examined TLR2 and TLR4 mRNA and protein expression and mechanism of their induction in monocytic cells under high-glucose conditions. RESEARCH DESIGN AND METHODS—High glucose (15 mmol/l) significantly induced TLR2 and TLR4 expression in THP-1 cells in a time- and dose-dependent manner (P < 0.05). High glucose increased TLR expression, myeloid differentiation factor 88, interleukin-1 receptor–associated kinase-1, and nuclear factor-κB (NF-κB) p65-dependent activation in THP-1 cells. THP-1 cell data were further confirmed using freshly isolated monocytes from healthy human volunteers (n = 10). RESULTS—Pharmacological inhibition of protein kinase C (PKC) activity and NADPH oxidase significantly decreased TLR2 and TLR4 mRNA and protein (P < 0.05). Knocking down both TLR2 and TLR4 in the cells resulted in a 76% (P < 0.05) decrease in high-glucose–induced NF-κB activity, suggesting an additive effect. Furthermore, PKC-α knockdown decreased TLR2 by 61% (P < 0.05), whereas inhibition of PKC-δ decreased TLR4 under high glucose by 63% (P < 0.05). Small inhibitory RNA to p47Phox in THP-1 cells abrogated high-glucose–induced TLR2 and TLR4 expression. Additional studies revealed that PKC-α, PKC-δ, and p47Phox knockdown significantly abrogated high-glucose–induced NF-κB activation and inflammatory cytokine secretion. CONCLUSIONS—Collectively, these data suggest that high glucose induces TLR2 and -4 expression via PKC-α and PKC-δ, respectively, by stimulating NADPH oxidase in human monocytes.
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            Endogenous ligands of Toll-like receptors.

            B Gao, M F Tsan (2004)
            Extensive work has suggested that a number of endogenous molecules such as heat shock proteins (hsp) may be potent activators of the innate immune system capable of inducing proinflammatory cytokine production by the monocyte-macrophage system and the activation and maturation of dendritic cells. The cytokine-like effects of these endogenous molecules are mediated via the Toll-like receptor (TLR) signal-transduction pathways in a manner similar to lipopolysaccharide (LPS; via TLR4) and bacterial lipoproteins (via TLR2). However, recent evidence suggests that the reported cytokine effects of hsp may be a result of the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) being responsible for the putative TLR ligands of hsp include failure to use highly purified hsp free of LPS contamination; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. Whether other reported putative endogenous ligands of TLR2 and TLR4 are a result of contamination of pathogen-associated molecular patterns is not clear. It is essential that efforts should be directed to conclusively determine whether the reported putative endogenous ligands of TLRs are a result of the endogenous molecules or of contaminant(s), before exploring further the implication and therapeutic potential of these putative TLR ligands.
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              Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

              Sara Reyna, Sangeeta Ghosh, Puntip Tantiwong … (2008)
              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 κB (IκB)/nuclear factor κB (NFκB). 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 (IκB/NFκB) 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 IκB/NFκB 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 IκBα content, an indication of elevated IκB/NFκB signaling. The increase in TLR4 and NFκB signaling was accompanied by elevated expression of the NFκB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IκB/NFκB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IκB/NFκB 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 NFκB. 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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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Care
                Journal ID (hwp): diacare
                Journal ID (pmc): dcare
                Journal ID (publisher-id): Diabetes Care
                Title: Diabetes Care
                Publisher: American Diabetes Association
                ISSN (Print): 0149-5992
                ISSN (Electronic): 1935-5548
                Publication date (Print): April 2010
                Publication date (Electronic): 12 January 2010
                Volume: 33
                Issue: 4
                Pages: 861-868
                Affiliations
                [1] 1Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento, California;
                [2] 2VA Medical Center of Northern California, Mather Field, California.
                Author notes
                Corresponding author: Mohan R. Dasu, ravi.dasu@ 123456ucdmc.ucdavis.edu .
                Article
                Publisher ID: 1799
                DOI: 10.2337/dc09-1799
                PMC ID: 2845042
                PubMed ID: 20067962
                SO-VID: bd121a67-cc25-4835-afd5-62c982ccf9ed
                Copyright © © 2010 by the American Diabetes Association.
                License:

                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.

                History
                Date received : 24 September 2009
                Date accepted : 6 January 2010
                Funding
                Funded by: National Institutes of Health
                Award ID: K24 AT 00596
                Categories
                Subject: Original Research
                Subject: Pathophysiology/Complications

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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