Elsevier

Cytokine

Volume 42, Issue 3, June 2008, Pages 312-316
Cytokine

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

https://doi.org/10.1016/j.cyto.2008.02.014Get rights and content

Abstract

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA1c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMAIR score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMAIR, proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.

Introduction

Interleukin-12 (IL-12)—a cytokine produced by antigen presenting cells like dendritic cells (DC), macrophages and natural killer (NK) cells—plays a critical role in cell-mediated immunity. IL-12 affects a variety of stages in the immune response: it prompts NK cells and T cells to produce pro-inflammatory cytokines, such as IFN-γ (interferon-γ), IL-2, IL-3 and TNF-α (tumor necrosis factor-α); it contributes to NK cell maturation [1], [2]; and, along with other pro-inflammatory factors, it stimulates CD4+CD25 T cell activation in the presence of regulatory T cells [3]. IL-12 also regulates naïve T cell differentiation into T helper type 1 lymphocytes (Th1), and inhibits differentiation into T helper type 2 lymphocytes (Th2) [1], [4]. It has been documented that increased systemic inflammatory activity in patients with CAD (coronary artery disease) is associated with a prominent Th1 response [5].

Current data suggest that IL-12 plays a critical role in the pathogenesis of type 1 diabetes [1], [6], but the significance of IL-12 changes in the blood of patients with type 2 diabetes remains unclear. It has been observed that IL-12 plasma concentrations are elevated in type 2 diabetics [7], and that IL-12 contributes to the process of atherosclerotic plaque formation and probably accelerates the development of macrovascular complications in type 2 diabetics, as well [8], [9]. Additionally, it has been noted that elevated glucose levels in diabetic animals stimulates inflammatory reactions related to IL-12 cytokine gene expression [10]. However, it is not known whether factors related to the course of type 2 diabetes, such as metabolic compensation, beta cell secretory dysfunction, and insulin resistance affect IL-12 concentrations.

Therefore, the present study was undertaken to assess the relationship between metabolic control, insulin resistance and IL-12 concentrations in the sera of type 2 diabetics.

Section snippets

Study groups

Basal studies were performed in the Department of Pharmacology at Poznan University of Medical Sciences, on 41 type 2 diabetic patients (19 women and 22 men). Their mean age was 66.8 years (range 33–85 years). The mean duration of diabetes was 7.7 years (range 0.5–19 years). All patients were being treated with gliclazide [Diaprel; Servier, twice daily 80 mg (31) or Diaprel MR; Servier, 30 mg daily (7)] or with glimepiride [Amaryl; Aventis Pharma, 2 mg twice daily (3)]. Therapeutic regimen for

Results

The characteristics of all the subjects, including diabetic patients, CAD patients and healthy controls are shown in Table 1, Table 2. Diabetic patients and patients with CAD were similar, in terms of body mass index and lipid profile. Patients without overt carbohydrate metabolism deterioration (healthy subjects and patients with CAD) had lower levels of fasting glycaemia than diabetics. Plasma 1,5-AG concentrations were significantly lower in diabetic patients versus either control group. The

Discussion

Currently available data about the pathogenesis of type 2 diabetes demonstrate that a very important feature of this disease is chronic inflammation [23], [24]. IL-12 is a pro-inflammatory cytokine, but its role in the pathogenesis and course of diabetes still is being assessed [2], [25]. It is well known that high levels of IL-12 in serum can stimulate T lymphocytes and NK cells proliferation and migration to atherosclerosis plaques [26], [27]. Moreover, Th1 predominance related to IL-12 high

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