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Insulin resistance determines phagocytic nicotinamide adenine dinucleotide phosphate oxidase overactivation in metabolic syndrome patients

Fortuño, Anaa; Bidegain, Julena; José, Gorka Sana; Robador, Pablo Aa; Landecho, Manuel Fb; Beloqui, Oscarb; Díez, Javiera,c; Zalba, Guillermoa

doi: 10.1097/HJH.0b013e32832b1e8f
Original papers: Metabolic aspects

Objective Metabolic syndrome (MetS) is associated with insulin resistance and increases the cardiovascular risk. Oxidative stress constitutes a potential mechanism that links insulin resistance and cardiovascular disease. The aim of this study was to analyze the relationship of NADPH oxidase activation with insulin resistance, and the effect of this interaction on the cardiovascular risk in MetS patients.

Methods NADPH oxidase-dependent superoxide production and expression was evaluated by luminescence and western blot, respectively, in peripheral blood mononuclear cells obtained from 125 patients with MetS. Insulin resistance was defined by the homeostasis model assessment index. Matrix metalloproteinase-9 was quantified by enzyme-linked immunosorbent assay in plasma samples. To ascertain the mechanisms involved in vivo, we performed in-vitro experiments in cultured macrophages.

Results Fifty-six percent of patients with MetS showed insulin resistance. Plasma matrix metalloproteinase-9 levels were higher (P < 0.05) in insulin-resistant patients than in patients with insulin sensitivity. NADPH oxidase-dependent superoxide production was augmented (P < 0.05) in insulin-resistant patients with respect to insulin-sensitive patients. The interaction between insulin resistance and abnormally high NADPH oxidase-mediated superoxide production was associated with the highest matrix metalloproteinase-9 values. Increased NADPH oxidase-dependent superoxide production was significantly associated with higher NADPH oxidase p22phox expression in insulin-resistant than in insulin-sensitive patients. Interestingly, insulin upregulated p22phox in peripheral blood mononuclear cells and in murine macrophages.

Conclusion Insulin resistance is associated with phagocytic NADPH oxidase activation. This association results in the highest cardiovascular risk in MetS patients.

aDivision of Cardiovascular Sciences, Center for Applied Medical Research, Spain

bDepartment of Internal Medicine, Spain

cDepartment of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain

Received 18 November, 2008

Revised 17 February, 2009

Accepted 2 March, 2009

Correspondence to Guillermo Zalba, PhD, Center for Applied Medical Research, Av. Pío XII 55, 31008 Pamplona, Spain Tel: +34 948 194 700; fax: +34 948 194 716; e-mail:

© 2009 Lippincott Williams & Wilkins, Inc.