Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes.
OBJECTIVE
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.


METHODS
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]).


RESULTS
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).


CONCLUSIONS
Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.
Steno Diabetes Center, Gentofte, Denmark. ltar@steno.dk
Lise
L
Tarnow
Peter
P
Hovind
Tom
T
Teerlink
Coen D A
CD
Stehouwer
Hans-Henrik
HH
Parving
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood* / Q000737:chemistry; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology* / Q000503:physiopathology; D003404:Creatinine / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D003925:Diabetic Angiopathies / Q000097:blood / Q000453:epidemiology* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood* / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors
D015415:Biomarkers; C487735:dimethylarginine; D001120:Arginine; D003404:Creatinine; D019001:Nitric Oxide Synthase