Dimethylarginines at the crossroad of insulin resistance and atherosclerosis Judit Zsuga a, 4 , Ja ´nos Tfrfk b , Ma ´ria T. Magyar a , Attila Valikovics c , Rudolf Gesztelyi d,e , A ´ gota Lenkei f , La ´szlo ´ Csiba a , Sa ´ndor Ke ´ki b , Miklo ´s Zsuga b , Da ´niel Bereczki a a Department of Neurology, University of Debrecen, PO Box 31, H-4012 Debrecen, Hungary b Department of Applied Chemistry, University of Debrecen, H-4012 Debrecen, Egyetem te ´r 1, Hungary c Department of Neurology, County Hospital, 3501 Miskolc, Szentpe ´teri kapu 72-76, Hungary d Department of Pharmacology, University of Debrecen, PO Box 8, H-4012 Debrecen, Hungary e Department of Pharmacodynamics, University of Debrecen, PO Box 8, H-4012 Debrecen, Hungary f Department of Clinical Chemistry, University of Debrecen, PO Box 70, H-4012 Debrecen, Hungary Received 3 April 2006; accepted 13 October 2006 Abstract We tested if asymmetric dimethylarginine (ADMA) contributes to the simultaneous evolution of atherosclerosis and insulin resistance. We investigated the significant predictors of insulin resistance in the context of atherosclerosis, focusing on the role ADMA, symmetric dimethylarginine (SDMA), and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. In a case-control study, 60 patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and sex-matched controls were recruited at a community-based neurosonologic laboratory. We found a strong positive association between the homeostasis model assessment of beta-cell function and insulin resistance and the ADMA/SDMA ratio that remained statistically significant even after adjusting for all significant and a priori identified determinants (b = 6.76; 95% confidence interval [CI], 2.13-11.39; P = .005). Interestingly, this relationship was even more pronounced in the atherosclerotic stratum (b = 8.29; 95% CI, 1.43-15.15; P = .019), whereas, on multiple linear regression, lack of association was seen in subjects free of carotid atherosclerosis (b = 1.39; 95% CI, À5.46 to 8.26; P = .671). We conclude that ADMA/SDMA ratio is a significant determinant of insulin resistance and may be a better parameter to monitor than ADMA alone. By accounting for the competition at the y+ transporters, ADMA/SDMA ratio could be an indicator of intracellular ADMA level. D 2007 Elsevier Inc. All rights reserved. 1. Introduction Evidences in support of asymmetric dimethylarginine (ADMA), the most significant endogenous nitric oxide synthase (NOS) inhibitor, being a cardiovascular risk molecule are constantly accumulating [1]. As the details of the mechanisms accompanying this effect are unraveling, attention is starting to divert toward the symmetrical stereoisomer of ADMA—symmetric dimethylarginine (SDMA) [2]. Symmetric dimethylarginine, although it lacks a direct inhibitory effect on NOS, may hinder the synthesis of nitric oxide by competing with both ADMA and l-arginine for cell entry via the concentrative y+ transporter. Albeit some studies failed to associate SDMA with all-cause mortality and fatal/nonfatal cardiovascular events [3,4], more sophisticated approaches focusing on SDMA have identified risks associated with its elevation [5,6]. Accordingly, in the multicenter Coronary Artery Risk Determination investigat- ing the Influence of ADMA Concentration (CARDIAC) study, SDMA contributed to risk stratification in patients whose ADMA level was below the threshold level (1.75 lmol/L) of increased risk for coronary heart disease [7]. Earlier, on the basis of clinical evidences and preclinical models using NOS inhibitors for inducing insulin resistance, our group has proposed that ADMA may contribute to the simultaneous evolution of atherosclerosis and insulin resistance by inhibiting the endothelial and the neuronal NOS of the anterior hepatic plexus, with the latter being associated with the regulation of insulin sensitivity [8]. Starting from this hypothesis, we set out to investigate the significant predictors of insulin resistance in the context of atherosclerosis, with special focus on the role ADMA, SDMA, and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. 0026-0495/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.metabol.2006.10.023 4 Corresponding author. Tel.: +36 30 625 0144; fax: +36 52 453 590. E-mail address: zsuga@king.pharmacol.dote.hu (J. Zsuga). Metabolism Clinical and Experimental 56 (2007) 394 – 399 www.elsevier.com/locate/metabol