title: Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study.
abstract: OBJECTIVE
  Although interleukin-1 receptor antagonist (IL-1Ra) treatment is associated with improved beta-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.
  
  
  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.
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
authors.forename: Markus
authors.initials: M
authors.lastname: Jokela
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Shipley
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brunner
authors.forename: Adam G
authors.initials: AG
authors.lastname: Tabák
mesh_terms: D000328:Adult; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood*; D008297:Male; D008875:Middle Aged
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein