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Previous Volume 356:1517-1526 April 12, 2007 Number 15 Next

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ABSTRACT

Background The expression of interleukin-1–receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1 in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis.

Methods In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1–receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic–euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers.

Results At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events.

Conclusions The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov] .)

Source Information

From the Steno Diabetes Center, Gentofte (C.M.L., A. Vaag, T.M.-P.), and Biostatistics, Novo Nordisk, Bagsvaerd (A. Vølund) — both in Denmark; the Clinic for Endocrinology and Diabetes, University Hospital Zurich and Center for Integrative Human Physiology (M.F., J.A.E., M.Y.D.), and the Department of Biostatistics, University of Zurich (B.S.) — both in Zurich; and the University of Lund, Lund (A. Vaag), and the Karolinska Institute, Stockholm (T.M.-P.) — both in Sweden.

Drs. Larsen, Faulenbach, Mandrup-Poulsen, and Donath contributed equally to this article.

Address reprint requests to Dr. Donath at the Division of Endocrinology and Diabetes, University Hospital, CH-8091 Zurich, Switzerland, or at marc.donath{at}usz.ch.

Full Text of this Article

Related Letters:

Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus
Malozowski S., Sahlroot J. T., Mandrup-Poulsen T., Seifert B., Donath M. Y.
Extract | Full Text | PDF  
N Engl J Med 2007; 357:302-303, Jul 19, 2007. Correspondence

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