Endocrine Pharmacology
Effects of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes

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Abstract

Endothelial dysfunction is thought to be a critical event in the pathogenesis of vasculopathy in type 2 diabetes and oxidant stress is a major etiological factor. Gliclazide, a second generation sulfonylurea, contains an azabicyclo-octyl ring, which has been described to have antioxidant properties. However, the effect of gliclazide on endothelial function is unknown. Therefore, in this study, we examined the effect of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes (diabetic group; n = 33). A control group of non-diabetic subjects was also enrolled (n = 25). All of the diabetic patients were treated with gliclazide for 12 weeks. Endothelial function was evaluated by flow-mediated vasodilation (FMD) before and after treatment. We also determined the number of circulating endothelial progenitor cells (EPCs), which were defined by CD45low/CD34+/VEGFR2+ and quantified by flow cytometry, because these cells may offer a new biomarker for circulatory diseases. Oxidative stress was evaluated in terms of the serum levels of malondialdehyde, superoxide dismutase and nitric oxide. FMD, circulating EPC count and superoxide dismutase activity were significantly lower in the diabetic group than in the control group at baseline (P < 0.05), and improved significantly following gliclazide treatment (P < 0.05). Malondialdehyde and nitric oxide levels were higher in the diabetic group than in the control group at baseline (P < 0.05), and decreased following gliclazide treatment. These results suggest that gliclazide could improve endothelial function in diabetes, which may be related to its antioxidant properties.

Introduction

The prevalence of type 2 diabetes has increased dramatically in China over the last two decades, meaning the prevention and treatment of diabetes are major issues for Chinese society (Li et al., 2008). In diabetic patients, endothelial dysfunction is thought to be a critical factor involved in vascular complications (Widlansky et al., 2003, Creager et al., 2003), which are the principal cause of morbidity and mortality in diabetes. Endothelial dysfunction includes arterial stiffness, inflammation, thrombosis, and impaired regulation of arterial tone and flow (Halcox et al., 2002). Flow-mediated vasodilation (FMD) is considered as an important marker of endothelial dilatory function in clinical studies of diabetes and vascular diseases (Widlansky et al., 2003).

Endothelial progenitor cells (EPCs), another marker of endothelial function, were discovered in 1997 as circulating cells with the ability to differentiate into mature endothelium and participate in neoangiogenesis (Asahara et al., 1997). EPCs, which share hematopoietic and endothelial lineage surface markers (Fadini et al., 2005a), are mobilized from bone marrow and specifically target sites of endothelial injury in some pathological conditions, and then stimulate angiogenesis and endothelial repair (Aicher et al., 2005, Takahashi et al., 1999). Therefore, the circulating EPC count is considered to be a predictor of endothelial function and cardiovascular health (Hill et al., 2003, Liao et al., 2010).

Gliclazide, a second generation sulfonylurea, seems to have antioxidant properties independent of its hypoglycemia action that may be mediated by its azabicyclo-octyl ring (O'Brien et al., 2000). It is now widely accepted that oxidative stress in the vasculature is a critical factor underlying endothelial dysfunction in diabetes. Some studies have also shown that antioxidant treatment could restore endothelial function (Tomasian et al., 2000). To date however, studies investigating the effects of gliclazide on endothelial function have mainly focused on inflammation and thrombosis in the endothelium (Mamputu and Renier, 2004). Accordingly, the effects of gliclazide on FMD and circulating EPCs in diabetic patients remain unknown.

Therefore, in this study, we tested the hypothesis that gliclazide could improve FMD and increase the number of circulating EPCs in type 2 diabetic patients via antioxidant activities.

Section snippets

Study subjects

Between August 2007 and December 2008, 33 Chinese patients with newly diagnosed type 2 diabetes (18 men and 15 women, aged 38–56 years) who were outpatients of the Endocrinology Department at Wuhan Union Hospital, participated in this study. A further 25 control subjects (14 men and 11 women) who took part in health examination at the hospital were randomly selected. Medical history, physical examination, blood biochemistry and clinical diagnosis were evaluated in all subjects. Subjects were

Baseline characteristics of the study population

The study population consisted of 33 newly diagnosed type 2 diabetic subjects and 25 sex-and age-matched control individuals. The diabetic patients were treated with gliclazide for about 12 weeks. Baseline clinical characteristics of both groups of subjects are summarized in Table 1. Compared with controls, the patients with newly diagnosed type 2 diabetes had significantly higher waist-to-hip ratio, fasting blood glucose, 2-hour blood glucose, HbA1C, fasting insulin, homeostasis model of

Discussion

Our present study revealed that, in type 2 diabetic patients, treatment with gliclazide for 12 weeks significantly reversed endothelial dysfunction, as evidenced by increases in FMD and the number of circulating EPCs, and improvements in oxidation–reduction status. These results are in accordance with those of another recent study by Sena et al. (2009). However, they reported the effects of gliclazide on oxidative status and NO-mediated vasodilation of aortic ring segments in Goto-Kakizaki rats.

Acknowledgment

This study was supported by grants from the Scientific Research Foundation from health department of Hubei Province (No. JX3A04).

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