Abstract

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

Research Design and Methods: Among 70 ambulatory patients with type 2 diabetes and A1C and body mass index higher than 7.5% and 27, respectively, randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blinded 39 week follow-up study. Primary outcome was change in betacell function following anakinra withdrawal. Analysis was done by intention-to-treat.

Results: Thirty-nine weeks following 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 to 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 of C-reactive protein (−3.2 mg/l [95% CI −6.2 to −1.1, P=0.014]) and of IL-6 (−1.4 ng/l [95% CI −2.6 to −0.3, P=0.036]) were maintained until end of study.

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