Insulin increases shedding of syndecan-1 in the serum of patients with type 2 diabetes mellitus
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.
References (37)
- et al.
Participation of high glucose concentrations in neutrophil adhesion and surface expression of adhesion molecules on cultured human endothelial cells: effect of antidiabetic medicines
J. Diabetes Complicat.
(2002) - et al.
Syndecans in wound healing, inflammation and vascular biology
Int. J. Biochem. Cell Biol.
(2007) - et al.
Leukocyte-mediated endothelial cell injury and death in the diabetic retina
Am. J. Pathol.
(2001) - et al.
Neutrophil beta2 integrins: moderators of life or death decisions
Trends Immunol.
(2005) - et al.
Regulated shedding of syndecan-1 and -4 ectodomains by thrombin and growth factor receptor activation
J. Biol. Chem.
(1997) - et al.
Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa
J. Biol. Chem.
(2000) - et al.
Serum syndecan-1: a new independent prognostic marker in multiple myeloma
Blood
(2000) - et al.
Pretreatment serum syndecan-1 levels and outcome in small cell lung cancer patients treated with platinum-based chemotherapy
Lung Cancer
(2003) - et al.
Global and societal implications of the diabetes epidemic
Nature
(2001) Treating type 2 diabetes—today's targets, tomorrow's goals
Diabetes Obes. Metab.
(2001)
Obesity, insulin resistance and diabetes—a worldwide epidemic
Br. J. Nutr.
Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994
Diabetes Care
Endothelial dysfunction and pathogenesis of diabetic angiopathy
Cardiovasc. Res.
Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death
Diabetes
The markers of inflammation and endothelial dysfunction in correlation with glycated haemoglobin are present in type 2 diabetes mellitus patients but not in their relatives
Glycoconj. J.
Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans
Annu. Rev. Cell Biol.
Functions of cell surface heparan sulfate proteoglycans
Annu. Rev. Biochem.
Syndecans in inflammation
Faseb J.
Cited by (31)
The effects of female sexual hormones on the endothelial glycocalyx
2023, Current Topics in MembranesHyperglycemia-induced effects on glycocalyx components in the retina
2021, Experimental Eye ResearchCitation Excerpt :As mentioned above, a significant loss of syndecan-1 is observed in intestinal and renal glomerular endothelial cells in hyperglycemia, and therefore, multiple tissues may be contributing sources of soluble syndecan-1 in the plasma. Previously, an increase in serum levels of syndecan-1 was detected in both diabetic patients and STZ-induced diabetic animals (Qing et al., 2015; J. B. Wang et al., 2009; J. B. Wang et al., 2013). In addition, vitreous levels of syndecan-1 escalated in proliferative diabetic retinopathy (PDR) patients, suggesting increased shedding of syndecan-1 (Abu El-Asrar et al., 2015).
Syndecan-4 is regulated by IL-1β in β-cells and human islets: Syndecan-4 in β-cells
2020, Molecular and Cellular EndocrinologyCitation Excerpt :Once released, this soluble ectodomain can circulate and compete with cell surface binding (Sanderson et al., 2005). Shedding occurs in response to external triggers such as growth factors (Subramanian et al., 1997), chemokines (Li et al., 2002; Brule et al., 2006; Charnaux et al., 2006), insulin (Wang et al., 2009), heparanase (Yang et al., 2007) and cell stress (Fitzgerald et al., 2000). Shedding occurs also as a constitutive process in cultured cells (Fitzgerald et al., 2000).
Endothelial glycocalyx biomarkers increase in patients with infection during Emergency Department treatment
2017, Journal of Critical CareCitation Excerpt :This was also true for ICU admission. Both syndecan-1 and hyaluronan concentrations can be increased by a range of chronic diseases, such as diabetes [39], renal disease [40] and congestive heart failure [41]. Given that cumulative comorbidities have also been associated with organ failure in sepsis [42], it is possible that comorbid disease burden is a significant confounder of EG biomarker concentrations.
Syndecans as cell surface receptors: Unique structure equates with functional diversity
2011, Matrix BiologyCitation Excerpt :A number of extracellular components, including EGF and cytokines, are involved in the regulation of syndecan shedding (Subramanian et al., 1997; Henry-Stanley et al., 2006). ADAM17 is known to increase shedding of syndecan-1 in inflammation (Pruessmeyer et al., 2010), and insulin increases the shedding of syndecan-1 in type II diabetes (Wang et al., 2009). Moreover, extra-embryonic syndecan-2 is reported to be involved in organ primordia migration and fibrillogenesis (Arrington and Yost 2009), and shed syndecan-1 produced by MMP-7-mediated cleavage increases wound healing by modulating integrin α2β1 (Chen et al., 2009).