Elevated Interleukin-18 Levels Are Associated With the Metabolic Syndrome Independent of Obesity and Insulin Resistance

Abstract

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.