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Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects.
- Source :
-
Diabetes care [Diabetes Care] 2010 Apr; Vol. 33 (4), pp. 861-8. Date of Electronic Publication: 2010 Jan 12. - Publication Year :
- 2010
-
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.<br />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.<br />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(epsilon)-(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-kappaB p65 expression in monocytes compared with control subjects. Furthermore, TLR-MyD88-NF-kappaB signaling resulted in elevated levels of cytokines (P < 0.05), but increased interleukin (IL)-1beta, interferon (IFN)-gamma, and endotoxin were not significant when adjusted for BMI.<br />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.
- Subjects :
- Adaptor Proteins, Vesicular Transport metabolism
Blotting, Western
Case-Control Studies
Chaperonin 60 metabolism
Enzyme-Linked Immunosorbent Assay
HMGB1 Protein metabolism
HSP72 Heat-Shock Proteins metabolism
Humans
Hyaluronic Acid metabolism
Immunoprecipitation
Interferon Regulatory Factor-3 metabolism
Interferon-gamma metabolism
Interleukin-1 Receptor-Associated Kinases metabolism
Interleukin-1beta metabolism
Monocytes metabolism
Myeloid Differentiation Factor 88 metabolism
Reverse Transcriptase Polymerase Chain Reaction
Toll-Like Receptor 2 genetics
Toll-Like Receptor 2 metabolism
Toll-Like Receptor 4 genetics
Toll-Like Receptor 4 metabolism
Toll-Like Receptors genetics
Transcription Factor RelA metabolism
Diabetes Mellitus, Type 2 metabolism
Toll-Like Receptors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1935-5548
- Volume :
- 33
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes care
- Publication Type :
- Academic Journal
- Accession number :
- 20067962
- Full Text :
- https://doi.org/10.2337/dc09-1799