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.

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.

FIG. 1.

A–D: Model-predicted IL-1Ra trajectories in nondiabetic and incident diabetic subjects. Year 0 denotes the time of diagnosis for case subjects and a randomly selected time point during follow-up for control subjects (noncases). All models were adjusted for age, sex, and ethnicity. Additional adjustment was performed for BMI (B), waist circumference (C), and fasting insulin (D). The table below the panels shows the number of measurements at each time point for both case and control subjects. Error bars represent 95% CIs around the values estimated by the fixed effect part of the mixed model presented in Table 4.