Circulating IL-18 concentration is associated with insulin sensitivity and glucose tolerance through increased fat-free mass

Aims/hypothesis: Knowledge of the factors which simultaneously contribute to insulin-resistance-related inflammation may contribute to early therapeutic targeting. IL-18 has recently been described as one of the factors which, in addition to insulin resistance, may also contribute to atherosclerosis. However, the source of IL-18 is not well characterised. Materials and methods: We aimed to study body composition ( bioelectric impedance), glucose tolerance (OGTT) and insulin sensitivity ( minimal model method) in relation to serum IL-18 ( ELISA) concentration in 144 otherwise healthy men aged 51.9 +/- 12.5 years. Results: In contrast to previous observations in women, circulating IL-18 was not significantly associated with BMI ( r=0.12, p=0.1) or WHR ( r=0.08, p=0.3). IL-18 was also not associated with absolute or percent fat mass ( bioelectric impedance, p>0.20) but, interestingly, it was significantly linked to fat-free mass ( p= 0.03). Serum IL-18 increased with each quartile of fat-free mass, corresponding to values of <= 64.2; > 64.2 to <= 71.6; > 71.6 to <= 80.9; and >= 80.9 kg (ANOVA, p< 0.0001). IL-18 was more closely associated with postload glucose during an OGTT ( p= 0.04) rather than with fasting glucose ( p= 0.1). HbA(1)c ( p= 0.03), HDL-cholesterol ( p= 0.04) and serum triglycerides ( p= 0.03) and parameters of systemic inflammation ( C-reactive protein, p= 0.02) were also significantly associated with circulating IL-18. Insulin sensitivity (minimal model analysis) was linked to circulating IL-18 (p= 0.01). In a multiple linear regression analysis this relationship remained significant after controlling for BMI, age and glucose tolerance status. In another model, both fat-free mass and insulin sensitivity contributed to 10% of IL-18 variance. Conclusions/interpretation: Fat mass does not seem to influence circulating IL-18, as initially proposed. In contrast, the fat-free mass compartment ( a well-known confounder in the evaluation of insulin sensitivity) may significantly contribute to the relationship between IL-18 and insulin action.