Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

  1. Claus M. Larsen, MD1,
  2. Mirjam Faulenbach, MD2,
  3. Allan Vaag, MD, PHD1,3,
  4. Jan A. Ehses, PHD2,
  5. Marc Y. Donath, MD2 and
  6. Thomas Mandrup-Poulsen, MD, PHD1,4,5
  1. 1Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark;
  2. 2Clinic for Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland;
  3. 3University of Lund, Lund, Sweden;
  4. 4Core Unit for Medical Research Methodology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark;
  5. 5Karolinska Institutet, Stockholm, Sweden.
  1. Corresponding author: Thomas Mandrup-Poulsen, tmpo{at}hagedorn.dk.
  1. C.M.L., M.F., M.Y.D., and T.M.-P. contributed equally to this study.

Abstract

OBJECTIVE Interleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses.

RESEARCH DESIGN AND METHODS Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m2 and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat.

RESULTS Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by −0.07 [95% CI −0.14 to −0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (−3.2 mg/l [−6.2 to −1.1], P = 0.014) and in IL-6 (−1.4 ng/l [−2.6 to −0.3], P = 0.036) were maintained until the end of study.

CONCLUSIONS IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.

Footnotes

  • Clinical trial reg. no. NCT00303394, clinicaltrials.gov.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received March 18, 2009.
    • Accepted June 8, 2009.
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  1. Diabetes Care vol. 32 no. 9 1663-1668
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