Insulin increases shedding of syndecan-1 in the serum of patients with type 2 diabetes mellitus

https://doi.org/10.1016/j.diabres.2009.08.002Get rights and content

Abstract

Aims

To detect the level of serum syndecan-1 of patients with type 2 diabetes.

Methods

Subjects with diabetes were categorized into 4 subgroups, oral-agents, insulin therapy for ≤1 month, 1–12 months, and >12 months. Serum syndecan-1 was detected by ELISA, and potential correlation between syndecan-1 levels and clinical characteristics was analyzed.

Results

Sixty-two diabetic patients and 20 healthy subjects (controls) were enrolled. Syndecan-1 in diabetic patients (24.616 ± 1.993 ng/ml) was higher than that of the controls (18.907 ± 2.638 ng/ml). The average concentration of syndecan-1 in the group of oral-agents, insulin therapy for ≤1 month, 1–12 months, and >12 months was 19.157 ± 2.556 ng/ml (n = 20), 24.447 ± 3.173 ng/ml (n = 23), 35.005 ± 4.749 ng/ml (n = 11), and 27.593 ± 8.304 ng/ml (n = 8), respectively. An association between serum syndecan-1 and intake of exogenous insulin was found (r = 0.266, p = 0.035). Serum syndecan-1 of insulin-therapy group (27.811 ± 2.669 ng/ml) enhanced significantly compared to that of the controls (p = 0.030) and that of the oral-agents group (p = 0.035). Syndecan-1 of the insulin therapy for 1–12 months group enhanced predominantly compared to that of the controls (p = 0.005) and the oral-agents group (p = 0.005).

Conclusions

Chronic inflammation and exogenous insulin usage increases serum syndecan-1 level. Exogenous insulin can promote shedding of syndecan-1 ectodomains to the serum in a time-dependent manner.

Introduction

Type 2 diabetes is increasing worldwide and is seen in ever-younger age groups [1], [2]. Approximately 150 million persons have type 2 diabetes worldwide today. It is estimated that diabetes will affect 300 million people by 2025 [3], [4]. Endothelial dysfunction plays key roles in patients with type 1 and type 2 diabetes, as well as in animal models of diabetes. Endothelial dysfunction contributes to the pathogenesis of both micro- and macroangiopathy of diabetes [5]. A prospective study showed that both inflammatory activity and endothelial dysfunction increased over time, and they were strongly interrelated [6]. Inflammation disrupts endothelium by mediating polymorphonuclear leukocyte (neutrophil)–vascular endothelial cell adhesion. It was demonstrated that high glucose concentrations significantly increase neutrophil–endothelial cell adhesion by increasing the surface expression of endothelial adhesion molecules, such as intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule-1, P-selectin, and E-selectin [7]. It is proved that ICAM-1, P-selectin and E-selectin in diabetic subjects increased [8]. However, it was unclear whether or not other adhesion molecules were involved in the pathogenesis of diabetes.

The heparin-related glycosaminoglycan heparin sulfate (HS) binds to and modifies the function of several molecules involved in the inflammatory process under physiological conditions. On the cell surface, proteoglycans of the syndecan family are the major sources of HS [9], [10]. In vitro experiments and studies have provided new insights in the role of the syndecans in inflammation [11]. As can be expected from the diversity of HS functions in the inflammatory process, syndecans affect the functional properties of chemokines, leukocytes, and endothelial cells in multiple ways [11].

Currently, there are four known mammalian syndecans, syndecan-1 through -4, which were encoded by distinct genes. Syndecan-1, also known as CD138, is the most extensively studied member of the syndecan family. Syndecan-1 is believed to be involved in the processes of cell growth, differentiation, adhesion, wound healing and inflammation [12]. Increasing evidence showed that syndecan-1 acts as a negative modulator of leukocyte–endothelial interactions [13].

Little is known about the alteration of serum syndecan-1 in patients with type 2 diabetes. In this study, we examined the level of serum syndecan-1 in diabetic patients, and investigated the correlation between serum syndecan-1 and clinical parameters.

Section snippets

Patients and samples

This research adhered to the principles of the Declaration of Helsinki for research involving human subjects. All serum samples and data were collected under an institutional review board-approved protocol with written informed consent from subjects. Complete clinical data were recorded at the 309th Hospital of Chinese People's Liberation Army. Peripheral venous blood samples were collected in sterile test tubes, centrifuged at 3000 × g for 10 min, and serum samples were stored at −70 °C.

Patients

Clinical parameters

The study comprised of 62 consecutive patients with type 2 diabetes and 20 consecutive healthy controls at the 309th Hospital of Chinese People's Liberation Army, Beijing, China, from 10 May 2008 to 13 January 2009 who had peripheral venous blood samples available.

In the 62 diabetic patients, 31 (50.0%) were male and 31 (50.0%) were female, with a mean age of 55.7 (range 30–84) years. Mean duration of diagnosis of diabetes was 6.8 (range 0.03–20) years. Of the 62 patients, 32 patients (50.8%)

Discussion

Inflammation and endothelial dysfunction are two interrelated factors to precede the development of diabetes [15]. Under inflammation conditions, increased leukocyte adhesion to the vasculature is a critical event in the damage of endothelial cells [16], [17]. Three families of adhesion molecules are known to be involved in the interaction between leukocytes and the endothelium of diabetes: immunoglobulin, integrin and selectin [18]. The involvement of another adhesion molecule, syndecans, in

Conclusions

This is the first study to report the level of serum syndecan-1 in persons with type 2 diabetes. Increased serum syndecan-1 level was detected in diabetes in vitro, and a higher serum syndecan-1 level is associated with the insulin intake, which suggests that chronic inflammation and insulin can increase the shedding of syndecan-1 ectodomains in diabetes. Furthermore, exogenous insulin promotes serum syndecan-1 shedding in a time-dependent manner.

Conflict of interest

There are no conflicts of interest.

Acknowledgements

We are grateful to the following nurses for their help in collecting of peripheral venous blood samples: Yan Zhang, Chun-mei Zhang, Ying-qin Xie, Ya-li Liu, Lin Zhang, Li-bo Yang, Shuang Guo.

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