Increased CD40 ligand and platelet–monocyte aggregates in patients with type 1 diabetes mellitus
Introduction
Diabetes mellitus markedly increases the risk of cardiovascular morbidity and mortality [1], [2]. Elevated levels of inflammatory cytokines, chemokines, adhesion molecules and platelet activation have been found both in type 1 and type 2 diabetes [2], [3], [4], [5]. However, the mechanisms involved in the development of this proinflammatory and prothrombotic state are complex and poorly understood.
CD40 ligand (L), and its receptor CD40, are expressed on a wide range of atheroma-associated cells. Ligation of CD40 by CD40L induces expression of cytokines, chemokines, adhesion molecules, matrix metalloproteinases and tissue factor [6], [7], [8]. In addition, soluble (s) CD40L can act as a platelet agonist and stabilize arterial thrombi [9]. Interruption of the CD40/CD40L dyad reduces atherosclerotic plaque formation and progression in hypercholesterolaemic mice [10], [11]. In clinical studies, patients with acute coronary syndromes express higher levels of CD40L [12] with elevated serum sCD40L concentrations identifying those at highest risk of future adverse cardiovascular events [13].
Platelet–monocyte aggregates have recently been demonstrated to be a sensitive measure of platelet activation [14]. Moreover, platelet–monocyte interactions are important in regulating monocyte expression and secretion of interleukin (IL)-1β, IL-8, monocyte chemoattractant protein (MCP)-1, Mac-1 and tissue factor [15], [16], [17]. In addition, platelet–monocyte aggregation promotes monocyte adhesion to activated endothelium and atherosclerotic lesion formation in apolipoprotein E-deficient mice [18].
The aim of the present study was to investigate whether CD40L expression and platelet–monocyte aggregates are increased in patients with type 1 diabetes.
Section snippets
Patients and controls
Twenty-two patients with type 1 diabetes were compared to 22 age- and sex-matched non-diabetic subjects. Exclusion criteria were as follows: age <18 years or >50 years, evidence of cardiovascular disease, intercurrent illness, surgery within the previous 2 months, systemic inflammatory disorder or malignancy, treatment with medication other than insulin, current smokers, hypertension (resting blood pressure of >140/90 mmHg or a previous history of hypertension requiring treatment), proteinuria
Results
Baseline characteristics of patients with type 1 diabetes and non-diabetic controls were similar except for fasting plasma glucose concentrations and HbA1c (Table 1). The mean duration since the diagnosis of diabetes was 6.6 ± 1.2 years.
Serum CRP (3.29 ± 0.9 mg/L versus 0.99 ± 0.2 mg/L, P = 0.01) and sCD40L (10.0 ± 1.4 ng/mL versus 4.6 ± 0.6 ng/mL, P = 0.006) concentrations were significantly increased in patients with type 1 diabetes (Fig. 1A and B). Serum CRP correlated with plasma glucose (r =
Discussion
We have shown that diabetes mellitus is associated with increased serum sCD40L concentrations, platelet surface expression of CD40L and platelet–monocyte aggregates. These important findings provide a link between hyperglycaemia, the proinflammatory and prothrombotic state, as well as the accelerated atherosclerosis that occurs in patients with diabetes mellitus.
Atherosclerosis is a chronic inflammatory disease and both type 1 and type 2 diabetes mellitus have been associated with increases in
Conclusions
We have shown that type 1 diabetes is associated with elevation of sCD40L, platelet surface expression of CD40L and platelet–monocyte aggregates. Glycaemic control appears to play a role in regulating the inflammatory response and platelet activation in these patients. Up regulation of CD40L and platelet monocyte interactions are likely to contribute to the prothrombotic and proinflammatory milieu found in patients with diabetes and may predispose to the associated accelerated atherogenesis.
Acknowledgements
Dr Scott Harding is supported by a grant from the British Heart Foundation (PG/2001/068). Dr Andrew Sommerfield is supported by research funding from Eli Lilly and Company Limited.
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