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Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery disease: a 4.5-year follow-up study.

ABSTRACT: Endothelial dysfunction, largely dependent on impaired nitric oxide bioavailability, has been reportedly associated with incident type 2 diabetes. Our aim was to test the hypothesis that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide formation, might be linked to future deterioration in glucose tolerance in stable coronary artery disease (CAD).We studied 80 non-diabetic men (mean age 55 +/- 11 years) with stable angina who underwent successful elective complex coronary angioplasty and were receiving a standard medical according to practice guidelines. Plasma ADMA and its structural isomer symmetric dimethylarginine (SDMA) were measured prior to coronary angiography. An estimate of insulin resistance by homeostasis model assessment (HOMA-IR index) was calculated from fasting insulin and glucose. Deterioration in glucose tolerance was defined as development of type 2 diabetes or progression from a normal glucose tolerance to impaired fasting glucose.Over a median follow-up of 55 months 11 subjects developed type 2 diabetes and 13 progressed to impaired fasting glucose. Incident deterioration of glucose tolerance was associated with ADMA (hazard ratio [HR] per 1-SD increment 1.64 [95% CI: 1.14--2.35]; P = 0.007), log (HOMA-IR index) (HR = 1.60 [1.16--2.20]; P = 0.004) and body-mass index (HR = 1.44 [0.95--2.17]; P = 0.08) by univariate Cox regression. ADMA (HR = 1.65 [1.14--2.38]; p = 0.008) and log (HOMA-IR index) (HR = 1.55 [1.10--2.17]; P = 0.01) were multivariate predictors of a decline in glucose tolerance. ADMA and SDMA were unrelated to body-mass index, HOMA-IR index, insulin or glucose.ADMA predicts future deterioration of glucose tolerance independently of baseline insulin resistance in men with stable CAD. Whether this association reflects a contribution of endothelial dysfunction to accelerated decline of insulin sensitivity, or represents only an epiphenomenon accompanying pre-diabetes, remains to be elucidated. The observed relationship might contribute to the well-recognized ability of ADMA to predict cardiovascular outcome.

SUBMITTER: Surdacki A

PROVIDER: S-EPMC3642017 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery disease: a 4.5-year follow-up study.

Surdacki Andrzej A Kruszelnicka Olga O Rakowski Tomasz T Jaźwińska-Kozuba Aleksandra A Dubiel Jacek S JS

Cardiovascular diabetology 20130101

<h4>Background</h4>Endothelial dysfunction, largely dependent on impaired nitric oxide bioavailability, has been reportedly associated with incident type 2 diabetes. Our aim was to test the hypothesis that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide formation, might be linked to future deterioration in glucose tolerance in stable coronary artery disease (CAD).<h4>Methods</h4>We studied 80 non-diabetic men (mean age 55 +/- 11 years) with stable angina who underwent ...[more]

PMID: 23578341

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Project description:Background and objectivesLevels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase, are elevated in kidney disease and associated with mortality in white European hemodialysis populations. Nitric oxide production and degradation are partially genetically determined and differ by racial background. No studies have measured asymmetric dimethylarginine in African Americans on dialysis and assessed whether differences exist in its association with mortality by race.Design, setting, participants, & measurementsAsymmetric dimethylarginine was measured in 259 patients on maintenance hemodialysis assembled from 2004 to 2012 in Boston area outpatient centers. Cox proportional hazards models were used to determine the association between asymmetric dimethylarginine and all-cause mortality, and an interaction with race was tested.ResultsMean (SD) age was 63 (17) years, 46% were women, and 22% were African American. Mean asymmetric dimethylarginine in non-African Americans was 0.79 µmol/L (0.16) versus 0.70 µmol/L (0.11) in African Americans (P<0.001); 130 patients died over a median follow-up of 2.3 years. African Americans had lower mortality risk than non-African Americans (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.50) that was robust to adjustment for age, comorbidity, and asymmetric dimethylarginine (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.69). An interaction was noted between race and asymmetric dimethylarginine (P=0.03), such that asymmetric dimethylarginine was associated with higher mortality in non-African Americans (adjusted hazard ratio, 1.29; 95% confidence interval, 1.06 to 1.57 per 1 SD higher asymmetric dimethylarginine) but not in African Americans (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28 to 1.18). Additional adjustment for fibroblast growth factor 23 partially attenuated the association for non-African Americans (adjusted hazard ratio, 1.22; 95% confidence interval, 0.98 to 1.50).ConclusionsAfrican Americans have lower asymmetric dimethylarginine levels and lower hazard for mortality compared with non-African Americans. Levels of asymmetric dimethylarginine did not explain lower hazard for mortality in non-African American patients. High asymmetric dimethylarginine was a risk factor for mortality exclusively in non-African Americans. Mechanisms explaining these relationships need to be evaluated.

Project description:BackgroundAsymmetric dimethylarginine (ADMA), which is significantly elevated in the plasma of cancer patients, is formed via intracellular recycling of methylated proteins and serves as a precursor for resynthesis of arginine. However, the cause of ADMA elevation in cancers and its impact on the regulation of tumor immunity is not known.MethodsThree mouse breast cell lines (normal breast epithelial HC11, breast cancer EMT6 and triple negative breast cancer 4T1) and their equivalent 3D stem cell culture were used to analyze the secretion of ADMA using ELISA and their responses to ADMA. Bone marrow-derived macrophages and/or RAW264.7 cells were used to determine the impact of increased extracellular ADMA on macrophage-tumor interactions. Gene/protein expression was analyzed through RNAseq, qPCR and flow cytometry. Protein functional analyses were conducted via fluorescent imaging (arginine uptake, tumor phagocytosis) and enzymatic assay (arginase activity). Cell viability was measured via MTS assay and/or direct cell counting using Countess III FL system.ResultsFor macrophages, ADMA impaired proliferation and phagocytosis of tumor cells, and even caused death in cultures incubated without arginine. ADMA also led to an unusual macrophage phenotype, with increased expression of arginase, cd163 and cd206 but decreased expression of il10 and dectin-1. In contrast to the severely negative impacts on macrophages, ADMA had relatively minor effects on proliferation and survival of mouse normal epithelial HC11 cells, mouse breast cancer EMT6 and 4T1 cells, but there was increased expression of the mesenchymal markers, vimentin and snail2, and decreased expression of the epithelial marker, mucin-1 in EMT6 cells. When tumor cells were co-cultured ex vivo with tumor antigen in vivo-primed splenocytes, the tumor cells secreted more ADMA and there were alterations in the tumor cell arginine metabolic landscape, including increased expression of genes involved in arginine uptake, metabolism and methylation, and decreased expression of a gene that is responsible for arginine demethylation. Additionally, interferon-gamma, a cytokine involved in immune challenge, increased secretion of ADMA in tumor cells, a process attenuated by an autophagy inhibitor.ConclusionOur results suggest initial immune attack promotes autophagy in tumor cells, which then secrete ADMA to manipulate macrophage polarization favoring tumor tolerance.

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Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery disease: a 4.5-year follow-up study.

Publications

Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery disease: a 4.5-year follow-up study.

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