dimethylarginine and Diabetic-Nephropathies

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathy, which could account for disabilities and high mortality rates in patients with diabetes. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic vascular complications have now become one of the most challenging health problems. Nitric oxide (NO) is a pleiotropic molecule critical to a number of physiological and pathological processes in humans. NO not only inhibits the inflammatory-proliferative reactions in vascular wall cells, but also exerts anti-thrombogenic and endothelial cell protective properties, all of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes. However, high amounts of NO produced by inducible NO synthase (iNOS) and/or peroxynitrite (ONOO(-)), a reactive intermediate of NO with superoxide anion are involved in pro-inflammatory reactions and tissue damage as well. This implies that NO is a janus-faced molecule and acts as a double-edged sword in vascular complications in diabetes. Further, NO is synthesized from l-arginine via the action of NO synthase (NOS), while NOS is blocked by endogenous l-arginine analogues such as asymmetric dimethylarginine (ADMA), a naturally occurring amino acid which is found in the plasma and various tissues. These findings suggest that amounts of NO locally produced, oxidative stress conditions and level of ADMA could determine the beneficial and detrimental effects of NO on vascular complications in diabetes. In this paper, we review the janus-faced aspects of NO in diabetic microangiopathy.

Topics: Animals; Arginine; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Humans; Nitric Oxide; Nitric Oxide Synthase Type II

Altered circulatory asymmetric and symmetric dimethylarginines have been independently reported in patients with end-stage renal failure suggesting their potential role as mediators and early biomarkers of nephropathy. These alterations can also be reflected in urine. Herein, we aimed to evaluate urinary asymmetric to symmetric dimethylarginine ratio (ASR) for early prediction of diabetic nephropathy (DN). In this cross-sectional study, individuals with impaired glucose tolerance (IGT), newly diagnosed diabetes (NDD), diabetic microalbuminuria (MIC), macroalbuminuria (MAC), and normal glucose tolerance (NGT) were recruited from Dr. Mohans' Diabetes Specialties centre, India. Urinary ASR was measured using a validated high-throughput MALDI-MS/MS method. Significantly lower ASR was observed in MIC (0.909) and MAC (0.741) in comparison to the NGT and NDD groups. On regression models, ASR was associated with MIC [OR: 0.256; 95% CI: 0.158-0.491] and MAC [OR 0.146; 95% CI: 0.071-0.292] controlled for all the available confounding factors. ROC analysis revealed ASR cut-point of 0.95 had C-statistic of 0.691 (95% CI: 0.627-0.755) to discriminate MIC from NDD with 72% sensitivity. Whereas, an ASR cut-point of 0.82 had C-statistic of 0.846 (95% CI: 0.800 - 0.893) had 91% sensitivity for identifying MAC. Our results suggest ASR as a potential early diagnostic biomarker for DN among the Asian Indians.

Topics: Adult; Aged; Albuminuria; Arginine; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Feasibility Studies; Female; Humans; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Tandem Mass Spectrometry

To investigate whether circulating asymmetric dimethylarginine (ADMA) levels are predictive of cardiovascular events, decline in glomerular filtration rate (GFR), end-stage renal disease (ESRD), and all-cause mortality in type 1 diabetic patients.. We performed a prospective observational follow-up study including 397 type 1 diabetic patients with overt diabetic nephropathy (243 men aged 42.1 +/- 10.5 years, GFR 76 +/- 34 ml/min per 1.73 m(2)) and a control group of 175 patients with longstanding type 1 diabetes and persistent normoalbuminuria (104 men aged 42.7 +/- 9.7 years, duration of diabetes 27.7 +/- 8.3 years). Patients were followed for a median 11.3 years (range 0.0-12.9) with yearly measurements of GFR ((51)Cr-EDTA plasma clearance) in patients with diabetic nephropathy. Endpoints were fatal and nonfatal cardiovascular disease (CVD), decline in GFR, ESRD, and all-cause mortality.. Among patients with diabetic nephropathy, 37 patients (19.4%) with ADMA levels below the median, compared with 79 patients (43.4%) above the median, suffered a major cardiovascular event during the follow-up period (P < 0.001). This effect persisted after adjustment for conventional CVD risk factors including baseline GFR (adjusted hazard ratio [HR] for elevated ADMA 2.05 [95% CI 1.31-3.20], P = 0.002). Furthermore, elevated ADMA levels predicted an increased rate of decline in GFR, development of ESRD, and all-cause mortality (P < 0.001). After adjustment for well-known progression promoters, including baseline GFR, the HR (adjusted) was 1.85 (95% CI 0.99-3.46, P = 0.055) for ESRD comparing upper and lower median ADMA levels.. Plasma ADMA levels predict fatal and nonfatal cardiovascular events in patients with type 1 diabetic nephropathy. Furthermore, increased ADMA levels tend to contribute to increased risk of progressive diabetic kidney disease.

Topics: Adult; Albuminuria; Arginine; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Male; Middle Aged

Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients.. ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD).. ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids.. Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.

Topics: Aged; Albuminuria; Arginine; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged

Topics: Albuminuria; Arginine; Cholesterol, HDL; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Foot; Hot Temperature; Humans; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Thrombomodulin; Vasodilation

Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy.. ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]).. In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05).. Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.

Topics: Adult; Arginine; Biomarkers; Blood Pressure; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Morbidity; Nitric Oxide Synthase