Markers of endothelial dysfunction in hyperglycaemic Asian Indian subjects Vijay Viswanathan * , C. Snehalatha, Mamtha B. Nair, A. Ramachandran Diabetes Research Centre, WHO Collaborating Centre for Research, Education and Training in Diabetes 4, Main Road, Royapuram, Chennai 600 013, India Received 5 December 2002; received in revised form 20 March 2003; accepted 25 March 2003 Abstract Objective: The aims of this study were the following: (1) to determine the levels of endothelin-1(ET1), soluble adhesion molecules like intracellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in different stages of glucose intolerance and to identify a suitable marker of endothelial dysfunction and (2) to determine the possible association of these biochemical parameters with diabetic complications and with impaired glucose tolerance (IGT). Research Design and Methods: In this cross-sectional study, plasma ET1, sICAM-1, and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 20 nondiabetic subjects, in 15 subjects with IGT, in 21 Type 2 diabetic subjects without any complication, and in 21 Type 2 diabetic patients with nephropathy and retinopathy. Results: Median ET1 levels were significantly elevated ( P = .004) in IGT subjects (0.31 fmol/ml) when compared with the nondiabetic subjects (0.11 fmol/ml). Subjects with nephropathy (0.50 fmol/ml) had significantly higher ( P = .002) ET1 values when compared with those without complications (0.40 fmol/ml). The levels of sICAM-1 and sVCAM-1 did not show any significant difference among the groups. ET1 showed correlation with age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), 2 h post glucose (2hPG), waist-to-hip ratio (WHR), total white blood corpuscles count, glycosylated haemoglobin (HbA1c), triglycerides (TG), very-low- density lipoprotein cholesterol (VLDLc), and hypertension (HTN). In the multiple linear regression analysis, plasma ET1 was significantly associated with the presence of Type 2 diabetes either with or without complications ( P < .0001and P = .0098, respectively), WHR ( P = .0063), and sVCAM-1 ( P = .0051). The total variance explained by the above-mentioned parameters was 55%. Conclusion: Elevated levels of ET1 were present in subjects with IGT and in Type 2 diabetic subjects. Such associations with sICAM-1 or sVCAM-1 in these subjects were not seen. ET1 could be an early marker of endothelial dysfunction, which appeared to occur even in the subclinical stages of hyperglycaemia. D 2004 Elsevier Science Inc. All rights reserved. 1. Introduction Type 2 diabetes is universally accepted to be a potent cardiovascular risk factor (Kannel & Larson, 1993). Im- paired glucose tolerance (IGT), considered to be a fore- runner of diabetes is also associated with several risk factors predisposing to atherogenesis(Haffner, 1998; LeFebvre & Scheen, 1998). Endothelial dysfunction precedes the devel- opment of atherosclerosis in Type 2 diabetes (Ross, 1993) and is also found in conditions such as hypertension (Mattei, Virdis, Ghiadoni, Taddei, & Salvetti, 1997), hypercholester- olaemia (Sorensen et al., 1994), smoking (Celermajer et al., 1996), and diabetes (Cosentino & Luscher, 1998). Factors leading to the development of endothelial dysfunction in diabetes include activation of protein kinase C, overexpres- sion of growth factors and/or cytokines, and oxidative stress. Different approaches, namely morphological, functional, and biological, may be used to assess endothelial integrity. Plasma levels of endothelin-1 (ET1) (Bluher, Unger, Ras- soul, Richter, & Paschke, 2002) and soluble adhesion mole- cules like intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) (Takahashi, Ghatei, Lam, O’Halloran, & Bloom, 1992) may reflect endothelial dysfunction. Endothelins (ETs) are a family of peptides with potent vasoconstrictor properties that have been isolated from the supernatant of cultured aortic endothelial cells (Yanagisawa et al., 1988). Three ET isoforms exist (ET1, ET2, ET3) (Inone et al., 1989), but ET1 is the only ET to be made by endothelial cell. sICAM-1 and sVCAM-1 are related mole- cules belonging to the immunoglobulin supergene family (Stauton, Marlin, Stratowa, Dustin, & Springer, 1988). These molecules are ligands for leukocyte integrins and 1056-8727/04/$ – see front matter D 2004 Elsevier Science Inc. All rights reserved. doi:10.1016/S1056-8727(03)00037-0 * Corresponding author. Tel.: +91-44-2595-49-13 to 15; fax: +91-44- 2595-49-19. E-mail address: dr_vijay@vsnl.com (V. Viswanathan). Journal of Diabetes and Its Complications 18 (2004) 47 – 52