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


CONCLUSIONS
Insulin resistance is associated with phagocytic NADPH oxidase activation. This association results in the highest cardiovascular risk in MetS patients.
Division of Cardiovascular Sciences, Center for Applied Medical Research, University Clinic, University of Navarra, Pamplona, Spain.
Ana
A
Fortuño
Julen
J
Bidegain
Gorka
G
San José
Pablo A
PA
Robador
Manuel F
MF
Landecho
Oscar
O
Beloqui
Javier
J
Díez
Guillermo
G
Zalba
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D010586:Phagocytes / Q000201:enzymology*; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D019255:NADPH Oxidases