Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance

Objective - Activated innate immunity is thought to be involved in the pathogenesis of metabolic syndrome and type 2 diabetes. Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine with important regulatory functions in the innate immune response. We sought to determine whether an elevated IL-18 concentration was a risk predictor for metabolic syndrome in a community population independent of obesity and hyperinsulinemia. Methods and Results - A representative general population, aged 27 to 77 years, without clinical diabetes was studied for clinical and biochemical risk factors for metabolic syndrome. Serum IL-18 concentration measured in 955 subjects correlated with metabolic syndrome traits including body mass index (BMI), waist circumference, triglyceride, high-density lipoprotein ( inversely), and fasting glucose and insulin levels ( all P < 0.001). Mean IL-18 levels rose progressively with the increasing number of metabolic risk factors ( ANOVA P <0.001). After adjusting for age, gender, BMI, and insulin levels, increasing IL-18 tertiles were associated with an odds ratio for metabolic syndrome of 1.0, 1.42, and 2.28, respectively ( P trend = 0.007). The graded risk relation was even stronger in nonobese subjects and not attenuated when adjusted for C-reactive protein and IL-6 levels. Conclusion - Our findings support the hypothesis that activation of IL-18 is involved in the pathogenesis of the metabolic syndrome.