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Abstract
Circulating asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, has been proposed as a biomarker for clinical outcome. Dimethylarginine dimethylaminohydrolase (DDAH) is the main enzyme responsible for ADMA metabolism and elimination. Adipose tissue ADMA concentrations and DDAH activity and their role in diabetes and obesity have not yet been investigated. In this study, we evaluated clinical microdialysis in combination with a sensitive analytical method (GC-MS/MS) to measure ADMA concentrations in extracellular fluid. Adipose tissue ADMA concentrations were assessed before and during an oral glucose tolerance test in lean healthy subjects and subjects with diabetes (n = 4 each), and in morbidly obese subjects before and after weight loss of 30 kg (n = 7). DDAH activity was determined in subcutaneous and visceral adipose tissue obtained during laparoscopic surgery (n = 5 paired samples). Mean interstitial ADMA concentrations did not differ between study populations (healthy 0.17 ± 0.03 μM; diabetic 0.21 ± 0.03 μM; morbidly obese 0.16 ± 0.01 and 0.17 ± 0.01 μM before and after weight loss, respectively). We did not observe any response of interstitial ADMA concentrations to the oral glucose challenge. Adipose tissue DDAH activity was negligible compared to liver tissue. Thus, adipose tissue ADMA plays a minor role in NO-dependent regulation of adipose tissue blood flow and metabolism.
Highlights
Endothelial function is already impaired in obesity and insulin resistance [1,2] and further deteriorates with the development of type 2 diabetes and cardiovascular disease [3,4]
We studied subjects with expected differences in interstitial asymmetrical dimethylarginine (ADMA) concentrations due to differences in body weight and glucose homeostasis
Circulating ADMA concentrations were lowest in normal weight healthy subjects and significantly higher in morbidly obese patients
Summary
Endothelial function is already impaired in obesity and insulin resistance [1,2] and further deteriorates with the development of type 2 diabetes and cardiovascular disease [3,4]. One of the main candidate molecules for the link between endothelial dysfunction, cardiovascular disease, and insulin resistance is the endogenous nitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) [8,9]. The association between elevated glucose and plasma ADMA was recently confirmed in human subjects [10]. A possible mechanism leading to increased ADMA concentrations is reduced DDAH activity through high glucose [12]. We assume that an acute increase in plasma glucose concentrations or alterations in insulin sensitivity will induce changes in interstitial ADMA concentrations in humans
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