Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes.
OBJECTIVE
Type 1 diabetes is a proinflammatory state characterised by increased levels of circulating biomarkers of inflammation and monocyte activity. We have shown increased Toll-like receptor 2 (TLR2) and TLR4 expression and signalling in monocytes from type 1 diabetic patients. Several endogenous ligands of TLR2 and TLR4 have been identified; however, there is a paucity of data on levels of these endogenous ligands in diabetes. Thus, the aim of this study was to examine circulating levels of exogenous/endogenous ligands of TLR2 and TLR4 in type 1 diabetic patients and to compare these with the levels in matched healthy controls.


METHODS
Healthy controls (n = 37) and type 1 diabetic patients (n = 34) were recruited, and a fasting blood sample was obtained. Circulating levels of endotoxin, heat-shock protein 60 (Hsp60), high-mobility group box 1 (HMGB1) and growth arrest-specific 6 (GAS6) proteins were assessed by ELISA, and TLR2 and TLR4 expression was determined by flow cytometry.


RESULTS
Levels of the classical TLR4 ligand, endotoxin, were significantly elevated in type 1 diabetic patients compared with those in matched controls. Hsp60 and HMGB1 concentrations were also significantly increased in the patients (p < 0.01 and p < 0.001, respectively). No significant differences were observed in GAS6.


CONCLUSIONS
We report the novel observation that levels of ligands of TLR2 and TLR4 are significantly elevated in type 1 diabetes, and this, in concert with hyperglycaemia, accounts for the increase in TLR2 and TLR4 activity, underscoring the proinflammatory state of type 1 diabetes.
Devaraj
S
S
Laboratory for Atherosclerosis and Metabolic Research, UC Davis Medical Center, Sacramento, CA 95817, USA.
Dasu
M R
MR
Park
S H
SH
Jialal
I
I
D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000097:blood; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007249:Inflammation / Q000209:etiology; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C495342:TLR2 protein, human; C493487:Tlr4 protein, mouse