Published online before print May 12, 2003, doi: 10.1161/01.CIR.0000074043.46437.44
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(Circulation. 2003;107:2664.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients
A Novel Target of Thiazolidinediones
From Cardiovascular Medicine (N.V., R.N., P.L., U.S.), Brigham and Women’s Hospital, Boston, Mass; Hospital Carlos III (D.V.), Madrid, Spain; Joslin Diabetes Center (A.B.G., E.H.), Boston, Mass; Beth Israel Deaconess Medical Center (A.V.), Boston, Mass; Epidemiología y Salud Pública, Facultad de Medicina (J.J.V.), Universidad de Navarra, Spain; Hospital Universitario San Carlos (M.R.B., A.F.-C.), Madrid, Spain; and The Diabetes and Nutrition Group of the Spanish Diabetes Association (A.L.C.-P.).
Correspondence to Peter Libby, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Background— Considerable evidence implicates the proinflammatory cytokine CD40 ligand (CD40L) in atherosclerosis and accumulating data link type 1 and 2 diabetes, conditions associated with accelerated atherosclerosis, to inflammation. This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L (sCD40L) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation.
Methods and Results— Subjects with type 1 (n=49) or type 2 diabetes (n=48) had higher (P<0.001) sCD40L plasma levels (6.56±3.27 and 6.67±2.90 ng/mL, respectively) compared with age-matched control groups (1.40±2.21 and 1.32±2.68 ng/mL, respectively). Multiple regression analysis demonstrated a significant (P<0.001) association between plasma sCD40L and type 1 as well as type 2 diabetes, independent of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, body mass index, gender, C-reactive protein, and soluble intracellular adhesion molecule-1. Furthermore, in a pilot study, administration of troglitazone (12 weeks, 600 mg/day), but not placebo, to type 2 diabetics (n=68) significantly (P<0.001) diminished sCD40L plasma levels by 29%. The thiazolidinedione lowered plasma sCD40L in type 2 diabetic patients with long-standing disease (>3 years) with or without macrovascular complications (-34% and -29%, respectively) as well as in type 2 diabetic patients with more recent (<3 years) onset of the disease (-27%; all P<0.05).
Conclusions— This study provides new evidence that individuals with type 1 or 2 diabetes have a proinflammatory state as indicated by elevated levels of plasma sCD40L. Troglitazone treatment of type 2 diabetic patients diminishes sCD40L levels, suggesting a novel antiinflammatory mechanism for limiting diabetes-associated arterial disease.
Key Words: atherosclerosis • diabetes mellitus • inflammation • immunology
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