The metabolic syndrome phenotype is associated with raised circulating Big endothelin-1 independently of coronary artery disease in type 2 diabetes

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Summary Background and objectives Insulin modulates key regulators of vascular tone, including endothelin-1 (ET-1), hence insulin resistance (IR) and/or hyperinsulinemia may contribute to the pathogenesis of hypertension and cardiovascular disease (CVD). Imbalance in ET-1/nitric oxide may link IR to CVD. Little is known on the relation between neurohormones, metabolic syndrome (MetS) categories (1–5/5) in type 2 diabetes (T2DM). We therefore sought to assess the relationship between neurohormonal profile, CVD and MetS in a large T2DM cohort, as well as the associations between neurohormones, insulinaemia, insulin sensitivity, CVD markers and events within MetS categories. Methods In 455 consecutive T2DM patients with or without MetS [MetS (+)/(−)] defined according to AHA/NHLBI , we assessed the following: MetS categories, HOMA-S, circulating Big-endothelin-1 (Big ET-1), natriuretic peptides and macroangiopathy [Macro (+)/(−)]. Results Big ET-1 was higher by 30%, in MetS (+) (median [IQ range]): 5.2 [4.3–6.0] pg ml −1 in MetS (−) ( n = 75) versus 6.7 [5.2–9.1] pg ml −1 in MetS (+) ( n = 380; P −1 in MetS (+) 3/5; 6.9 [5.1–9.4] pg ml −1 in MetS (+) 4/5 and 7.3 [5.6–9.5] pg ml −1 in MetS (+) 5/5 (NS). The incremental difference in Big ET-1 between MetS (+) and MetS (−) was found out both in the absence or presence of macroangiopathy: 4.55 [4.03–5.25] pg ml −1 in MetS (−) Macro (−) versus 5.70 [4.60–7.50] pg ml −1 in MetS (+) Macro (−) ( P −1 in MetS (−) Macro (+) versus 7.60 [5.80–10.13] pg ml −1 in MetS (+) Macro (+) ( P Conclusions Big ET-1 is raised in T2DM patients with MetS, and its level proceeds stepwise to MetS categories. Elevated Big ET-1 is present in all categories of MetS patients, with or without macroangiopathy. The ascent in Big ET-1 found in MetS (+) without macrovascular disease is of the same magnitude as that conferred by the presence of macroangiopathy.