Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients -: A novel target of thiazolidinediones

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.