Abstract
BackgroundEndothelial 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).MethodsWe 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 medication 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.ResultsOver 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.ConclusionsADMA 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.
Highlights
Endothelial dysfunction, largely dependent on impaired nitric oxide bioavailability, has been reportedly associated with incident type 2 diabetes
symmetric dimethylarginine (SDMA) correlated to estimated glomerular filtration rate (eGFR) (r = −0.66, P < 0.001) and body-mass index (BMI) to log-transformed values of Homeostasis model assessment for insulin resistance (HOMA-insulin resistance (IR)) index (r = 0.37, P = 0.001) and of fasting insulin (r = 0.30, P = 0.007)
Log (HOMA-IR index) (r = −0.18, P = 0.12), plasma dimethylarginines were unrelated to BMI, HOMA-IR index, fasting insulin or glucose levels (P > 0.3)
Summary
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). Endothelial dysfunction, a predecessor of atherosclerotic plaques and adverse cardiovascular (CV) events, is largely mediated by depressed bioavailability of nitric oxide (NO) [1]. The endogenous inhibitor of NO formation, asymmetric dimethylarginine (ADMA), is associated with endothelial dysfunction and adverse outcome predictor including allcause mortality and CV events in patients with coronary artery disease (CAD) and in the general population [12]. There are conflicting data on relations between ADMA and the magnitude of IR in human studies [14,15,16,17,18,19,20,21,22,23].
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