Elevated Levels of Interleukin-6 in Young Adults With Type 1 Diabetes Without Clinical Evidence of Microvascular and Macrovascular Complications

The past decade has been characterized by growing interest in the idea that atherosclerosis is an inflammatory disease, and by the finding that serum levels of markers of inflammation can be used to predict the risk of cardiovascular events (1). Elevated concentrations of acute-phase reactants, such as C-reactive protein, soluble intercellular adhesion molecule-1, and fibrinogen, are found in patients with acute coronary syndromes and are predictors of future risk in apparently healthy individuals (1,2,3). The inflammatory cytokine interleukin-6 (IL-6) is a powerful inducer of the hepatic acute-phase response, and it has been proposed to be a central mediator in the pathogenesis of coronary heart disease through a combination of autocrine, paracrine, and endocrine mechanisms (4). In fact, in a recent study, serum levels of IL-6 were predictive of the risk of myocardial infarction in apparently healthy individuals, and although the levels of IL-6 were strongly correlated with the levels of C-reactive protein, the association between IL-6 and the risk of myocardial infarction remained significant, even after adjustment for the C-reactive protein level (5).

There is little and somewhat conflicting information regarding the impact of the diabetic state per se on serum IL-6, particularly in type 1 diabetic patients. Serum levels of IL-6 have been found to be normal (6) or higher (7) in type 1 diabetic individuals compared with those in control subjects. However, in these studies no information was available on macrovascular complications, smoking habit, blood pressure, or plasma lipids of the participants, which are all factors known to adversely affect serum IL-6 levels (1,4,7). In the present study, we endeavored to evaluate a selected group of lean, nonsmoking, normotensive, normolipidemic young type 1 diabetic patients who were without any clinical evidence of microvascular and macrovascular complications.

We compared serum levels of IL-6 and fibrinogen in 20 young adults with type 1 diabetes who regularly attended our diabetes clinic with those of 20 healthy volunteers who were matched for age (30 ± 1.8 vs. 31 ± 1.7 years), sex (M/F = 11/9 vs. 11/9), BMI (23.4 ± 0.7 vs. 23.5 ± 0.8 kg/m²), systolic (127 ± 2 vs. 126 ± 2 mmHg) and diastolic blood pressure (80 ± 1 vs. 81 ± 2 mmHg), and lipids (total cholesterol 4.6 ± 0.1 vs. 4.8 ± 0.2 mmol/l, triglycerides 1.03 ± 0.2 vs. 1.04 ± 0.1 mmol/l). All of the participants were nonsmokers. The average glycometabolic control of diabetic patients was fairly good (HbA_1c 6.2 ± 0.2%); the diabetes duration was 12.2 ± 2 years. None of the patients had diabetic retinopathy (by ophthalmoscopy), sensorimotor neuropathy (by biothesiometer), or nephropathy (by urinary albumin excretion rate). To exclude the presence of clinical macrovascular complications, a 12-lead resting electrocardiogram, measurement of ankle brachial pressure index, and carotid ultrasonography were performed in all of the diabetic patients.

Serum levels of IL-6 (ELISA-kit; Bender MedSystems Diagnostics, Vienna) and fibrinogen (IL-test-PT-fibrinogen HS; Instrumentation Laboratory, Lexington, MA) were markedly elevated in type 1 diabetic patients versus healthy control subjects (2.81 ± 0.5 vs. 1.36 ± 0.6 pg/ml, P < 0.001, and 3.24 ± 0.2 g/l vs. 2.41 ± 0.1 g/l, P < 0.05, respectively). Although the strongest correlate of IL-6 in these data was fibrinogen concentration (r = 0.58, P < 0.01), the serum levels of IL-6 remained markedly higher in diabetic patients (by ∼106%) than in healthy control subjects, even after adjustment for this factor. On the contrary, the difference in fibrinogen concentration observed between the two groups disappeared when allowance was made for serum IL-6 levels. This finding probably reflects the fact that IL-6, along with other cytokines, is a primary stimulant for the hepatic production of acute-phase proteins, such as fibrinogen and C-reactive protein (1,4). Plasma HbA_1c concentration had a marginal, but not significant, correlation with IL-6 levels (r = 0.39, P = 0.08).

Overall, therefore, the present results indicate that in young type 1 diabetic individuals with a good glycometabolic control and without any clinical evidence of microvascular and macrovascular complications, there is a marked increase of serum levels of IL-6 when compared with a matched-group of lean, nonsmoking, normotensive, and normolipidemic healthy control subjects. The present findings suggest that the increase of serum IL-6 levels observed in type 1 diabetic patients may be at least partly independent of the presence of clinical microvascular and macrovascular complications, cigarette smoking, or other traditional coronary risk factors and that other specific and diabetes-related mechanisms may be involved, such as advanced glycosylation end products (8). The evidence from this and other studies further supports the possibility that in young adults with type 1 diabetes, there is a low-level chronic inflammatory state, as reflected by levels of serum IL-6, that may play a key role in the early stages of atherogenesis and in the development of microvascular disorders. This hypothesis lends itself to testing the use of interventions to influence IL-6 secretion and actions.