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Stühlinger MC, Abbasi F, Chu JW, et al. Relationship Between Insulin Resistance and an Endogenous Nitric Oxide
Synthase Inhibitor. JAMA. 2002;287(11):1420–1426. doi:10.1001/jama.287.11.1420
Author Affiliations: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif. Dr Stühlinger is now with the Division of Cardiology, University of Innsbruck, Innsbruck, Austria.
Context 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.
Design, Setting, and Subjects 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.
Intervention 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.
Main Outcome Measures 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) µmol/L
(P = .001).
Conclusion 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
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