Accelerated Increase in Serum Interleukin-1 Receptor Antagonist Starts 6 Years Before Diagnosis of Type 2 Diabetes

Whitehall II Prospective Cohort Study

  1. Adam G. Tabák2,5
  1. 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany;
  2. 2Department of Epidemiology and Public Health, University College London, London, U.K.;
  3. 3Department of Metabolic Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany;
  4. 4Steno Diabetes Center, Gentofte, Denmark;
  5. 5Semmelweis University Faculty of Medicine, 1st Department of Medicine, Budapest, Hungary.
  1. Corresponding author: Christian Herder, christian.herder{at}
  1. M.C. and C.H contributed equally to this study.


OBJECTIVE Although interleukin-1 receptor antagonist (IL-1Ra) treatment is associated with improved β-cell function and glycemic control in patients with type 2 diabetes, its role in the development of type 2 diabetes remains unclear. We used repeated measurements to characterize IL-1Ra trajectories in individuals who developed type 2 diabetes.

RESEARCH DESIGN AND METHODS This case-cohort study, nested within the Whitehall II cohort, was based on 335 incident type 2 diabetes cases and 2,475 noncases. We measured serum IL-1Ra levels at up to three time points per individual and estimated retrospective trajectories of IL-1Ra before diabetes diagnosis (case subjects) or end of follow-up (control subjects) using multilevel analysis. Models were adjusted for age, sex, and ethnicity.

RESULTS IL-1Ra levels were already higher in the case than control subjects 13 years before diabetes diagnosis/end of follow-up (mean [95% CI] 302 [290–314] vs. 244 [238–249] pg/ml). In control subjects, IL-1Ra levels showed a modest linear increase throughout the study period. In case subjects, IL-1Ra trajectories were parallel to those in control subjects until 6 years (95% CI 7.5–4.5) before diagnosis and then rose steeply to 399 (379–420) pg/ml at the time of diagnosis (P < 0.0001 for slope difference). Adjustment for BMI and waist circumference as time-varying covariates had little impact on these trajectories.

CONCLUSIONS We show elevated IL-1Ra levels for 13 years and an accelerated increase during the last 6 years before type 2 diabetes diagnosis, indicating the presence of an anti-inflammatory response that may act to counterbalance the metabolic and immunologic disturbances that precede type 2 diabetes.


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    • Received August 12, 2009.
    • Accepted February 6, 2010.

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