The past decade has been characterized by growing interest in the idea that atherosclerosis is an inflammatory disease. Interaction of the multipotent immunomodulator CD40 ligand (CD40L) with its receptor CD40 has emerged as an important contributor to the inflammatory processes that lead to atherosclerosis and thrombosis. CD40 and CD40L are expressed on endothelial and smooth muscle cells, monocytes, and platelets, and CD40-CD40L interaction has been shown to promote a wide array of prothrombotic and inflammatory effects both in vitro and in vivo (1). In addition to the cell-associated form, CD40L also exists in a soluble form, which is fully active biologically, termed soluble CD40L (sCD40L). Elevated sCD40L levels are found in patients with acute coronary syndromes (2) and are predictive of increased risk of future cardiovascular events in clinically healthy women (3).
At present, little is known regarding the impact of the diabetic state itself on sCD40L levels, particularly in type 1 diabetic patients. It has been reported in only one recent study (4), in which both type 1 and type 2 diabetic patients were enrolled, that type 1 diabetic subjects (n = 49) had significantly higher sCD40L levels than control subjects. Similar results were found in a type 2 diabetic group (4); however, in that report the study population also included type 1 diabetic patients with clinically manifest macro- and microvascular complications, or who were taking antihypertensive and hypolipidemic drugs, or who were smokers, which are all factors known to adversely affect plasma inflammatory markers. Therefore, we believe that the results of this study should be interpreted with some degree of caution to draw firm conclusions regarding the adverse effects of diabetes itself on sCD40L levels.
In this pilot study, we endeavored to evaluate a selected group of lean, normotensive, normolipidemic, nonsmoking, young type 1 diabetic patients without any clinical evidence of chronic complications. We compared serum sCD40L levels (ELISA kit; Bender MedSystems Diagnostics) in 27 young adults with type 1 diabetes regularly attending our diabetes clinic with those of 19 healthy volunteers who were matched for age (mean ± SD) (31 ± 9 vs. 32 ± 6 years), sex (M/F 18/9 vs. 12/7), BMI (23.5 ± 2 vs. 23 ± 3 kg/m2), systolic (125 ± 12 vs. 123 ± 10 mmHg) and diastolic (80 ± 7 vs. 80 ± 5 mmHg) blood pressure, and lipids (total cholesterol 4.7 ± 0.8 vs. 4.9 ± 0.8 mmol/l, triglycerides 1.2 ± 1 vs. 1.1 ± 0.6 mmol/l). All of the participants were nonsmokers. The average glycemic control of patients was good (HbA1c 6.5 ± 1%), and their average duration of diabetes was of 10.6 ± 7 years. None of the patients had retinopathy (by ophthalmoscopy), sensorimotor neuropathy (by biothesiometer), or nephropathy (by urinary albumin excretion rate). To exclude the presence of clinical macroangiopathy, a resting electrocardiogram, measurement of ankle brachial pressure index, and carotid ultrasonography were performed in all of the diabetic patients.
Serum sCD40L concentrations of type 1 diabetic patients were substantially superimposable on those of healthy control subjects (2.35 ± 1.1 vs. 2.39 ± 0.9 ng/ml, comparison by Mann-Whitney U test). In the control group, sCD40L levels did not correlate significantly with other variables. In the diabetic group, sCD40L correlated positively with age (Spearman’s coefficient = 0.53; P < 0.01), and sP-selectin concentration (Spearman’s coefficient = 0.70; P < 0.001), whereas it did not correlate with sex, BMI, blood pressure, plasma lipids, HbA1c, and fibrinogen concentrations.
Overall, therefore, our results indicate that young type 1 diabetic individuals with good glycemic control and without clinically manifest chronic complications have sCD40L levels substantially similar to those of a matched group of lean, normotensive, normolipidemic, and nonsmoking healthy control subjects. The apparent discordance of our results with those recently reported by Varo et al. (4) may be partly explained by significant differences in the study population, including chronic complication status, degree of glycemic control, and atherogenic risk profile of patients. Our data do not exclude, obviously, the possibility that sCD40L plays an important part in the pathophysiology of macro- and microvascular complications of diabetes through its multiple inflammatory and prothrombotic effects, including platelet activation (2), as confirmed by the strong association of sCD40L with sP-selectin concentration observed in our study. This hypothesis lends itself to testing using interventions to influence sCD40L secretion and actions (such as antiplatelet treatment with abciximab). Nevertheless, the evidence from this and other studies (4) supports the hypothesis that the increase of sCD40L levels in type 1 diabetic patients can, at least in part, be explained by the presence of clinical micro- and macrovascular complications, smoking, or other traditional coronary risk factors. Interpretation of our results, however, requires care because of the relatively small number of patients. Future studies using larger cohorts will be needed to validate this hypothesis.
