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

Background: 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). Methods: 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 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. Results: 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. Conclusions: 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.