Elsevier

Life Sciences

Volume 77, Issue 2, 27 May 2005, Pages 149-159
Life Sciences

Effect of diabetic duration on serum concentrations of endogenous inhibitor of nitric oxide synthase in patients and rats with diabetes

https://doi.org/10.1016/j.lfs.2004.10.062Get rights and content

Abstract

This study was designed to investigate the effect of diabetic duration on serum concentrations of endogenous inhibitor of nitric oxide synthase NG, NG-asymmetric dimethylarginine (ADMA) in patients and rats with diabetes, and to determine whether elevated endogenous ADMA is implicated in endothelial dysfunction or macroangiopathy in diabetes. Experimental diabetic model was induced by a single intraperitoneal injection of streptozotocin to male Sprague-Dawley rats and fed for 2-, 4- and 8-week, respectively. Type 2 diabetic patients with different diabetic duration were recruited from Xiangya Hospital. Plasma glucose and serum ADMA levels were measured in both patients and rats. Moreover, endothelium-dependent relaxation of thoracic aortas and some parameters of metabolic control were examined in rats. Serum ADMA concentrations were significantly elevated in type 2 diabetic patients compared with healthy subjects (3.44 ± 0.40 vs 1.08 ± 0.14 μmol/L, n = 50 in diabetic patients and n = 40 in healthy subjects, P < 0.01). The serum levels of ADMA in patients with macroangiopathy were higher than the patients without macroangiopathy (P < 0.01). But no difference was observed in serum ADMA concentrations between groups of patients with different diabetic duration. Similarly, serum levels of ADMA in diabetic rats were also significantly elevated at 2-week duration compared with duration-matched control (3.71 ± 0.20 vs 1.04 ± 0.23 μmol/L, n = 5 ∼ 6, P < 0.01). This elevation of ADMA was retained to 4- and 8-week (3.54 ± 0.76 vs 0.95 ± 0.06 μmol/L for 4-week, 3.21 ± 0.50 vs 1.03 ± 0. 09 μmol/L for 8-week, n = 5 ∼ 6, all P < 0.01) and remained unchanged among three diabetic groups. The elevation of ADMA was accompanied by impairment of endothelium-dependent relaxation and poor metabolic control in diabetic rat. These results first reveal that the extent of elevation in serum ADMA in both rats and patients with diabetes is not proportion with the length of their diabetic duration but rather with the metabolic control of this disease. Elevated endogenous ADMA may be implicated in diabetes-induced endothelial dysfunction and macroangiopathy. This study is helpful to prevention and treatment of diabetic-induced endothelial dysfunction or macroangiopathy.

Introduction

Epidemiological studies have shown that diabetes mellitus is associated with accelerated atherosclerosis and an increased prevalence of cardiovascular diseases, which have become the principal cause of morbidity and mortality in patients with diabetes mellitus. Endothelial dysfunction is a critical and initiating factor for the development of diabetic vascular disease. Endothelial dysfunction is characterized by impaired function of the endothelium, associated with decreased production of nitric oxide (NO), reduced endothelium-dependent vasorelaxation in response to acetylcholine. A number of studies have confirmed that endothelium-dependent vasodilatation is impaired in animal models and patients with diabetes mellitus (Rodríguez-Mañas et al., 1998, Vehkavaara et al., 2000). Exposure of normal blood vessels to elevated glucose in vitro also cause similar impairment of endothelium-dependent relaxation observed in diabetes (Tesfamariam et al., 1990). But the mechanisms by which hyperglycemia impairs endothelium-dependent vasodilator function are still complex and poorly understood.

It is well documented endothelium-derived NO is a potent, endogenous antiatherogenic molecule. In addition to mediating the endothelium-dependent vasorelaxation, NO interferes with key events in the development of atherosclerosis, such as monocyte adhesion and migration to vessel wall, platelet aggregation, and vascular smooth muscle proliferation (Cooke, 2000). Therefore, the reduction of available NO would result in endothelial dysfunction and predispose people to vascular disease. NO is synthesized from L-arginine by nitric oxide synthase (NOS), and NG, NG-asymmetric dimethylarginine (ADMA), an L-arginine analogue, has been recognized as an endogenous competitive inhibitor of NOS (Vallance et al., 1992). There is increasing evidence that serum concentrations of NOS inhibitor ADMA were significantly elevated in experimental diabetic animal models (Xiong et al., 1997, Masuda et al., 1999) and type 2 diabetic patients, which was involved in the vascular functional damages and morphological changes associated with diabetes (Abbasi et al., 2001, Lin et al., 2002). These results suggest that elevated endogenous ADMA may be a contributor for the endothelial dysfunction and diabetic vascular complications. Therefore, to determine the change of endogenous ADMA levels in the different stages of diabetic duration is helpful to prevention and treatment of diabetic-induced endothelial dysfunction or macroangiopathy. In this study, we sought to explore the influence of diabetic duration on serum concentration of endogenous NOS inhibitor, and to determine the relationship between the elevated endogenous ADMA and diabetes-induced endothelial dysfunction and macroangiopathy in streptozotocin-induced diabetic rats and type 2 diabetic patients with different diabetic duration.

Section snippets

Materials

All chemicals were of the highest purity available. Streptozotocin, ADMA, phenylephrine, acetylcholine and sodium nitroprusside were purchased from Sigma Chemical Co. (St Louis. MO, USA). Thiobarbituric acid was obtained from Fluka (Milwaukee, WI, USA). The commercial kits of plasma glucose, glycosylated serum protein, and creatinine are the production of the Baoding Changcheng Clinical Agent Co. (Hebei, China), the Nanjing Jiancheng Bioengineering Institute (Jiangsu, China), and Zhongsheng

Patient characteristics

There is no significant difference in age and gender of diabetic patients between group with macroangiopathy and group without macroangiopathy. In 25 diabetic patients with macroangiopath, 11 patients were hypertension, 6 patients were coronary heart disease, and 8 patients were the both. In addition, there were 12 patients with nephropathy in the group with macroangiopathy, and there were 10 patients with nephropathy in 25 diabetic patients without macroangiopathy. The mean of systolic blood

Discussion

The present study confirms previous observations that endogenous ADMA levels were significantly elevated in serum of streptozotocin-induced diabetic rats (Xiong et al., 1997) and type 2 diabetic patients, which may be implicated in the endothelial dysfunction (Abbasi et al., 2001, Lin et al., 2002). In addition, this study investigated for the first time the change in serum concentrations of endogenous inhibitor of NOS at different diabetic duration, and found that the length of diabetic

Conclusions

In conclusion, the present study suggest that elevated endogenous inhibitor of NOS may be a contributor to endothelial dysfunction and macroangiopathy in diabetes, and reveals for the first time that the extent of elevation in serum ADMA in both rats and patients with diabetes is not proportion with the length of their diabetic duration but rather with the metabolic control of this disease.

Acknowledgments

This study was supported by the grants from the Natural Science Research Foundation of China (30271507 and 39970848).

References (19)

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