Aims/hypothesis: The pathophysiology of type 2 diabetes involves pro-inflammatory pathways. We tested the hypothesis that IL-18 predicts future diabetes cases.
Methods: We used a nested case-control design based in the Nurses' Health Study. Baseline blood samples were collected between 1989 and 1990. Questionnaires to assess body weight, lifestyle (physical activity, diet, smoking) and diabetes diagnosis were sent out and assessed biennially (follow-up until 2002). Cases (n = 1,012) were defined as women developing type 2 diabetes at least 1 year after blood sampling. Control women (n = 1,081) were matched to cases by age, date of blood draw, fasting status and race. We calculated the RR (95% CI) of type 2 diabetes in quintiles of IL-18 using conditional logistic regression with the first quintile as referent; adjustments included matching factors, diabetes risk factors, BMI, adipokine levels (adiponectin, resistin) and inflammatory proteins (C-reactive protein, tumour necrosis factor receptor 2 (TNFalpha-R2) and IL-6).
Results: Higher IL-18 levels were associated with increased risk of developing diabetes, even after adjustment for matching factors and multiple diabetes risk factors: being in the highest quintile of IL-18 was associated with a RR of 1.75 (1.41-2.18) for diabetes relative to the first quintile (p < 0.0001 for trend). Significant trends in association were still observed after adjustment for BMI (RR 1.44 [1.15-1.80], p < 0.0001 for trend) and adiponectin levels (RR 1.28 [1.02-1.60], p = 0.006 for trend). Further adjustment for inflammatory markers in a sub-sample did not significantly change the results.
Conclusions/interpretation: Elevated IL-18 levels are associated with higher risk of diabetes. This association is independent of usual risk factors, including BMI and adipokine levels.