Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precede the Onset of Type 2 Diabetes

Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precede the Onset of Type 2 Diabetes The Whitehall II Study Christian Herder , PHD 1 , Eric J. Brunner , PHD 2 , Wolfgang Rathmann , MD, MSPH 3 , Klaus Strassburger , PHD 3 , Adam G. Tabák , MD 2 4 , Nanette C. Schloot , MD 1 5 and Daniel R. Witte , PHD 2 6 1 Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Institute for Diabetes Research, Düsseldorf, Germany 2 Department of Epidemiology and Public Health, University College London, London, U.K. 3 Institute of Biometrics and Epidemiology, German Diabetes Center at Heinrich Heine University, Leibniz Institute for Diabetes Research, Düsseldorf, Germany 4 Semmelweis University, Budapest, Hungary 5 Center for Internal Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany 6 Steno Diabetes Center, Gentofte, Denmark Corresponding author: Christian Herder, christian.herder{at}ddz.uni-duesseldorf.de Abstract OBJECTIVE —Interleukin-1 receptor antagonist (IL-1Ra), a natural inhibitor of interleukin-1β, has been shown to improve β-cell function and glycemic control in patients with type 2 diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra are associated with incident type 2 diabetes during more than 10 years of follow-up. RESEARCH DESIGN AND METHODS —We measured serum IL-1Ra concentrations in a nested case-control study (181 case and 376 age-, sex-, and BMI-matched normoglycemic control subjects) within the Whitehall II cohort (U.K.). RESULTS —IL-1Ra concentrations were higher in case subjects ( P = 0.0006) and associated with incident type 2 diabetes (odds ratio for a 1-SD increase of IL-1Ra 1.48 [95% CI 1.21–1.80]). This association remained significant after adjustment for multiple potential confounders but was attenuated by adjusting for 2-h glucose. CONCLUSIONS —Our findings indicate that individuals who will develop type 2 diabetes are characterized by a complex immune activation that also includes upregulation of the anti-inflammatory cytokine IL-1Ra. Footnotes Published ahead of print at http://care.diabetesjournals.org on 10 December 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charg