Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients

Abstract

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.

Beyond Hyperglycemia in Diabetes: Role of Statin Treatment on Thrombogenesis Triggered by Inflammation

“…They show an increase of the soluble form of CD40 ligand (sCD40L) in patients with T2D, confirming previously published observations in both type 1 and 2 diabetes [15][16][17].…”

Constitutive and regulated expression and secretion of interferon-γ-inducible protein 10 (IP-10/CXCL10) in human adipocytes

“…44 It has been described before that PPARg agonists have a profound anti-inflammatory effect and reduce serum or plasma levels of acute phase proteins, soluble CD40 ligand and TNFa, which are associated with type 2 diabetes and/or atherosclerosis. [45][46][47] Future studies will have to show whether antidiabetic or lipid-lowering drugs affect systemic or local IP-10 levels and what the clinical relevance of their effect on IP-10 expression is.…”

An immune origin of type 2 diabetes?

“…Here, again, polymorphisms in immune genes modulate risk, implying a pathogenetic significance for immune gene products Table 4 Interventions that have an impact on the inflammatory state Inflammatory mediators whose concentrations are reduced by weight loss and/or physical exercise [190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207] CRP, TNF-α, soluble TNF-α receptor 2, IL-6, IL-18, MCP-1, PAI-1, t-PA, soluble ICAM-1, soluble VCAM-1, P-selectin Inflammatory mediators whose concentrations are reduced by glucose-lowering drugs [186,188,[208][209][210][211][212][213][214][215][216][217] Sulphonylurea: TNF-α Metformin: CRP Glitazones: CRP, SAA, TNF-α, soluble CD40 ligand, PAI-1 Insulin: CRP, IL-1, IL-6, TNF-α, soluble ICAM-1, MCP-1, PAI-1 SAA Serum amyloid A, t-PA tissue plasminogen activator, VCAM-1 vascular cell adhesion molecule-1 [171][172][173]. Where studied, the upregulation of inflammatory mediators was linked to increased oxidative stress, impaired mitochondrial function and abnormal cholesterol metabolism [174][175][176].…”