Insulin Resistance, ADMA Levels, and Cardiovascular Disease

The article by Stühlinger et al¹ in this issue of THE JOURNAL deserves to be read at least twice by physicians involved in the care of patients with cardiovascular disease. Two readings are needed not because the article is difficult to fathom, but because the study demonstrates a potentially important relationship between insulin resistance and plasma concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Elevated ADMA levels have been observed in various conditions, including hypertension, dyslipidemia, hyperglycemia, hyperhomocysteinemia, and renal failure, and are believed to be one cause of endothelial dysfunction in these conditions.² Elevated plasma ADMA concentrations are also associated with an increased risk of cardiovascular disease.³

The objectives of the study by Stühlinger et al were to evaluate a possible relationship between tissue insulin sensitivity and plasma ADMA levels, and to determine whether pharmacological treatment designed to increase insulin sensitivity could modulate ADMA concentrations. The authors enrolled 64 healthy nondiabetic volunteers—48 with normal blood pressure and 16 with hypertension—in a cross-sectional study. Then, in a substudy, 7 insulin resistant hypertensive patients were studied before and after administration of the insulin-sensitizing agent rosiglitazone.

The study demonstrated a positive relationship between insulin resistance and plasma ADMA concentrations, independent of other factors that typically are associated with insulin resistance and risk of coronary heart disease. For example, plasma ADMA concentrations were not increased in hypertensive patients unless these individuals also were insulin resistant. Plasma ADMA levels were positively correlated with fasting triglyceride levels, but not with low-density lipoprotein (LDL) cholesterol levels. In addition, the patients with high blood pressure and insulin resistance who were treated with rosiglitazone were noted to have enhanced insulin sensitivity and an associated decrease in plasma ADMA concentrations.

Various mechanisms have been shown to alter plasma ADMA concentration.^{4 - 8} ADMA is formed by enzymes called protein arginine N-methyltransferases (PRMTs). The expression of endothelial cell PRMTs is upregulated in the presence of native or oxidized LDL cholesterol, suggesting a novel mechanism by which plasma ADMA concentration may be elevated in hypercholesterolemia.⁴ Another metabolic pathway for ADMA involves the enzyme dimethylarginine dimethylaminohydrolase (DDAH).^{5 - 6} DDAH selectively hydrolyzes ADMA to L-citrulline and dimethylamine, so that the higher the DDAH activity, the lower the ADMA levels. Conversely, inhibition of DDAH activity leads to increased ADMA concentrations.^{5 - 6}

Although the pathways by which ADMA is synthesized and metabolized have yet to be fully elucidated, ADMA has been associated with endothelial dysfunction. For example, ADMA decreases endothelial NOS activity and increases endothelial oxidative stress and monocyte adhesiveness,⁸ processes that are important in the development and progression of coronary atherosclerosis and its equivalent in other vascular beds.⁹ Therefore, the association of ADMA with an increased risk of cardiovascular disease and acute coronary events is not surprising.¹⁰

Insulin resistance is closely associated with a constellation of other cardiovascular risk factors, including abdominal obesity, hypertension, hypertriglyceridemia, and low levels of high-density lipoprotein (HDL) cholesterol, now known collectively as the metabolic syndrome.^{11 - 12} In patients with reduced sensitivity to insulin, endothelial function is compromised: nitric oxide–mediated endothelium-dependent vasodilatation is impaired, plasma concentrations of plasminogen activator inhibitor 1 and endothelin 1 are increased, as is monocyte adhesiveness.¹ The authors suggest that elevated ADMA concentration may play a role in promoting the endothelial dysfunction observed in insulin resistance. The fact that an insulin sensitizing agent was able to reduce plasma ADMA levels suggests that increased plasma ADMA levels may be the result rather than the cause of insulin resistance.

The clinical importance of the findings of Stühlinger et al is apparent when patients who are seen every day in medical practice are considered. These patients reflect the characteristics of the American population, which is gradually becoming older and more obese. A recent report suggested that the prevalence of the metabolic syndrome, which includes the likelihood of insulin resistance, increases with age, affecting more than 40% of those older than 60 years.¹³ Based on age-adjusted estimates, about a quarter of the population has the metabolic syndrome, representing about 47 million Americans.¹³ In addition, the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) has drawn specific attention to the importance of this syndrome as a new target of risk-reduction therapy.¹¹

The cornerstones of therapy for the metabolic syndrome include weight control and appropriate physical activity.¹³ Use of drugs such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may represent another therapeutic avenue. In a post hoc analysis of the Scandinavian Simvastatin Survival Study (4S), patients with increased LDL cholesterol and triglyceride levels and decreased HDL cholesterol levels were more likely than patients with isolated high LDL cholesterol levels to have characteristics of the metabolic syndrome.¹⁴ These patients were at an even higher risk for cardiovascular events, and received greater benefit from simvastatin therapy than did patients with isolated increased LDL cholesterol levels. In the Cholesterol and Recurrent Events (CARE) trial, patients with impaired fasting glucose were at increased risk for coronary events, which was substantially reduced by HMG-CoA reductase therapy.¹⁵ The mechanism(s) by which statins may exert effects on the endothelium, independent of their lipid-lowering properties, are currently under intense scrutiny.¹⁶ Reductions in markers of inflammation and endothelial activation (such as von Willebrand factor, leukocytes, C-reactive protein, and p-selectin) observed in statin-treated patients¹⁷ might contribute to their clinical benefits. The effects of HMG-CoA reductase inhibitors on plasma ADMA levels have not been studied. Experimental data suggesting that drugs that enhance insulin sensitivity, such as metformin and the thiazolidinediones, may also have beneficial effects on the endothelium are intriguing.^{18 - 19}

The endothelium, long considered merely a group of cells passively lining the blood vessels, in reality is a major regulatory organ contributing a nonadhesive luminal surface, limiting smooth muscle proliferation and mediating immune and inflammatory processes in vessel walls. The loss of endothelial dependent vasodilatation is considered the first evidence of atherosclerosis in the affected vessel. Clearly, endothelial dysfunction is a harbinger of cardiovascular disease, a fact deserving greater appreciation in clinical practice.²⁰

The study by Stühlinger et al adds to the evidence indicating that ADMA is elevated in many disorders, appears to be a component of the endothelial dysfunction that accompanies them, and is not directly associated with other risk factors. Even though measuring plasma ADMA levels is difficult at present, future technological advances may permit this marker to be readily quantified. However, it remains to be seen whether an increase in plasma ADMA levels will be a major cardiovascular risk factor, signaling the need for intervention.²⁰ Until then, additional investigation into the complex relationships among ADMA, insulin resistance, and endothelial dysfunction hold promise for a further understanding of the risks and the evolving therapies for cardiovascular disease.