Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

Marliss, Errol B.; Chevalier, Stéphanie; Gougeon, Réjeanne; Morais, José A.; Lamarche, Marie; Adegoke, Olasunkanmi A. J.; Wu, Guoyao

doi:10.1007/s00125-005-0066-6

Cited by 124 publications

(102 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Whereas de novo protein synthesis by the liver has been suggested to explain the rapid increase in cholesterol seen after the onset of proteinuria, 31 we show that proteinuria is also associated with increased ADMA formation, which in turn is thought to be an important inducer of insulin resistance. 11, 26 Several limitations of our study should be discussed. Foremost, the cross-sectional nature of the study prevents any conclusion about causality.…”

Section: Discussionmentioning

confidence: 92%

“…Of interest for future studies, in this study ADMA and SDMA were both elevated most in the amyloidosis patients with marked proteinuria (Table 2), supporting a similar finding in diabetic patients without renal disease. 26 Furthermore, after adjustment for ADMA the significant association between the degree of proteinuria and FMD was lost (Table 4).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction

Yılmaz¹,

Sönmez²,

Sağlam³

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Asymmetric dimethyl-arginine (ADMA), a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of nitric oxide synthesis. The increased protein turnover that accompanies proteinuric secondary amyloidosis may increase circulating levels of ADMA, and this may contribute to endothelial dysfunction. We performed a cross-sectional study of 121 nondiabetic proteinuric patients with normal GFR (including 39 patients with nephrotic-range proteinuria and secondary amyloidosis) and 50 age-, sex-, and BMI-matched healthy controls. The proteinuric patients had higher levels of serum ADMA, symmetric dimethyl-arginine (SDMA), high-sensitivity C-reactive protein (hsCRP), and insulin resistance (homeostasis model assessment index) than controls. Compared with controls, brachial artery flow-mediated dilatation (FMD), serum L-Arginine, and the L-Arginine/ADMA ratio were significantly lower among proteinuric patients, suggesting greater endothelial dysfunction. When patients with secondary amyloidosis were compared with patients with glomerulonephritis who had similar levels of proteinuria, those with amyloidosis had higher ADMA and SDMA levels and lower L-Arginine/ADMA ratios and FMD measurements (P Ͻ 0.001 for all). Finally, even after adjusting for confounders, ADMA level correlated with both proteinuria and the presence of secondary amyloidosis, and was an independent predictor of FMD. We propose that ADMA synthesis may be increased in chronic kidney disease, especially in secondary amyloidosis, and this may explain part of the mechanism by which proteinuria increases cardiovascular morbidity and mortality.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction

Yılmaz¹,

Sönmez²,

Sağlam³

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…In this regard, intracellular accumulation of ADMA has been implicated as a causative factor in the development of a variety of pathological conditions through the impairment of the normal physiological functions of NO (25,35,41,55). However, questions still remain regarding the levels of endogenous methylarginines required for NOS inhibition.…”

Section: Discussionmentioning

confidence: 99%

Evidence for the Pathophysiological Role of Endogenous Methylarginines in Regulation of Endothelial NO Production and Vascular Function

Cardounel

Cui

Samouilov

et al. 2007

Journal of Biological Chemistry

225

172

View full text Add to dashboard Cite

In endothelium, NO is derived from endothelial NO synthase (eNOS)-mediated L-arginine oxidation. Endogenous guanidinomethylated arginines (MAs), including asymmetric dimethylarginine (ADMA) and N G -methyl-L-arginine (L-NMMA), are released in cells upon protein degradation and are competitive inhibitors of eNOS. However, it is unknown whether intracellular MA concentrations reach levels sufficient to regulate endothelial NO production. Therefore, the dose-dependent effects of ADMA and L-NMMA on eNOS function were determined. Kinetic studies demonstrated that the K m for L-arginine is 3.14 M with a V max of 0.14 mol mg The biological significance of guanidino-methylated arginine derivatives has been known since the inhibitory actions of N G -methyl-L-arginine (L-NMMA) 3 on macrophage induced cytotoxicity were first demonstrated. It was subsequently realized that these effects were mediated through inhibition of NO release (1). NO has been demonstrated as a critical effector molecule in the maintenance of vascular function (2-4). In the vasculature, NO is derived from the oxidation of L-Arg, catalyzed by the constitutively expressed enzyme, eNOS (5-7). This endothelial-derived NO diffuses from the vascular endothelium into the smooth muscle cell layer where it activates soluble guanylate cyclase leading to smooth muscle relaxation (2-4). In addition to its role in the maintenance of vascular tone, NO helps to maintain the anti-atherogenic character of the normal vascular wall. NO, in concert with various cell signaling molecules, has been demonstrated to maintain smooth muscle cell quiescence and as such, counteracts pro-proliferative agents, specifically those involved in the propagation of athero-proliferative disorders (8 -14). As such, eNOS dysfunction is an early symptom of vascular disease and is manifested through insufficient NO bioavailability. Several potential causes of NO deficiency in disease settings have been proposed. Among these, high circulating levels of the endogenous methylarginine NOS inhibitor asymmetric dimethylarginine (ADMA) has been hypothesized to be of particular importance (15)(16)(17)(18)(19)(20)(21). In neurons and the brain, it has been shown that the methyl arginine L-NMMA is also present, however, the levels of this methylarginine have not been previously considered in studies evaluating vascular dysfunction (22).ADMA and L-NMMA are endogenous inhibitors of NOS and are derived from the proteolysis of methylated arginine residues on various proteins. The methylation is carried out by a group of enzymes referred to as protein-arginine methyltransferase (23). Subsequent proteolysis of proteins containing methylarginine groups leads to the release of free methylarginine into the cytoplasm, and if sufficient levels are reached NO production from NOS would be inhibited (24, 25). To date, six different isoforms of the enzyme have been identified with each

show abstract

“…This would potentially contribute to endothelial dysfunction and hypertension, which frequently associate with both conditions. The main putative mechanisms for lower NO bioavailability in obesity and/or diabetes-related conditions include 1) decreased NOS expression (396); 2) increased levels of endogenous inhibitors (99,277); 3) increased cogeneration of O 2…”

Section: Ros Generationmentioning

confidence: 99%

Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species

Bashan¹,

Kovsan²,

Kachko³

et al. 2009

Physiological Reviews

481

373

View full text Add to dashboard Cite

Regulated production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) adequately balanced by antioxidant systems is a prerequisite for the participation of these active substances in physiological processes, including insulin action. Yet, increasing evidence implicates ROS and RNS as negative regulators of insulin signaling, rendering them putative mediators in the development of insulin resistance, a common endocrine abnormality that accompanies obesity and is a risk factor of type 2 diabetes. This review deals with this dual, seemingly contradictory, function of ROS and RNS in regulating insulin action: the major processes for ROS and RNS generation and detoxification are presented, and a critical review of the evidence that they participate in the positive and negative regulation of insulin action is provided. The cellular and molecular mechanisms by which ROS and RNS are thought to participate in normal insulin action and in the induction of insulin resistance are then described. Finally, we explore the potential usefulness and the challenges in modulating the oxidant-antioxidant balance as a potentially promising, but currently disappointing, means of improving insulin action in insulin resistance-associated conditions, leading causes of human morbidity and mortality of our era.

show abstract

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

Cited by 124 publications

References 51 publications

ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction

ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction

Evidence for the Pathophysiological Role of Endogenous Methylarginines in Regulation of Endothelial NO Production and Vascular Function

Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species

Contact Info

Product

Resources

About