Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.
BACKGROUND
Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and increased risk of cardiovascular disease. Several cardiovascular risk factors are associated with reduced sensitivity to insulin, but elevated ADMA concentrations have not been fully linked to the metabolic syndrome.


OBJECTIVE
To evaluate the relationship between insulin sensitivity and plasma ADMA concentrations, and to determine whether a pharmacological treatment that increases insulin sensitivity would also modulate ADMA concentrations.


METHODS
Cross-sectional study, containing a nonrandomized controlled trial component, of 64 healthy volunteers without diabetes (42 women, 22 men; 48 with normal blood pressure and 16 with hypertension), which was conducted at a university medical center between October 2000 and July 2001.


METHODS
Rosiglitazone (4 mg/d for 4 weeks and then 4 mg twice daily for 8 weeks), an insulin-sensitizing agent, was given to 7 insulin-resistant subjects with hypertension. These subjects were studied before and after 12-week treatment.


METHODS
Insulin sensitivity measured by the insulin suppression test, and fasting plasma levels of low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, glucose, insulin, and ADMA concentrations.


RESULTS
Plasma ADMA concentrations were positively correlated with impairment of insulin-mediated glucose disposal in nondiabetic, normotensive subjects (r = 0.73; P<.001). Consistent with the metabolic syndrome, ADMA levels were also positively correlated with fasting triglyceride levels (r = 0.52; P<.001) but not with low-density lipoprotein cholesterol levels (r = 0.19; P =.20). Plasma ADMA concentrations increased in insulin-resistant subjects independent of hypertension. Pharmacological treatment improved insulin sensitivity and reduced mean (SD) plasma ADMA concentrations from 1.50 (0.30) to 1.05 (0.33) micromol/L (P =.001).


CONCLUSIONS
A significant relationship exists between insulin resistance and plasma concentrations of ADMA. Pharmacological intervention with rosiglitazone enhanced insulin sensitivity and reduced ADMA levels. Increases in plasma ADMA concentrations may contribute to the endothelial dysfunction observed in insulin-resistant patients.
Stühlinger
Markus C
MC
Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94305, USA.
Abbasi
Fahim
F
Chu
James W
JW
Lamendola
Cindy
C
McLaughlin
Tracey L
TL
Cooke
John P
JP
Reaven
Gerald M
GM
Tsao
Philip S
PS
D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D002318:Cardiovascular Diseases; D003430:Cross-Sectional Studies; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D024821:Metabolic Syndrome / Q000502:physiology*; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012044:Regression Analysis; D012307:Risk Factors; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014665:Vasodilator Agents / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008074:Lipoproteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase