title: Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia. Effects in healthy subjects, and type 1 and type 2 diabetes mellitus.
abstract: Diabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r= 0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (~2-fold, 2-4 hours). Insulin inhibited by ~30% LPS-induced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TF-PCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.
authors: Anamika
authors: A
authors: Singh
authors: Guenther
authors: G
authors: Boden
authors: A. Koneti Rao, M.B.B.S., Temple University School of Medicine, Sol Sherry Thrombosis Research Center, 3400 North Broad Street, Philadelphia, PA 19140, USA, Tel.: +1 215 707 4684, Fax: +1 215 707 2783, E-mail: koneti@temple.edu.
authors: A Koneti
authors: AK
authors: Rao
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D001786:Blood Glucose / Q000378:metabolism*; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D006946:Hyperinsulinism / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000276:immunology; D007328:Insulin / Q000097:blood*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood / Q000276:immunology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000097:blood*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D013925:Thromboplastin
keywords: Diabetes mellitus; Toll-like receptor-4; hyperglycaemia; hyperinsulinaemia; tissue factor
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