Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes

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. Treatment with recombinant IL-1Ra improves glycemia and beta-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/m(2) 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 beta-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.

Figures

Figure 1

Enrollment and outcome. Of the 70 patients who underwent randomization, 67 completed 13 weeks of anakinra or placebo treatment and were included in the present 39-week follow-up study. Of the former anakinra- and placebo-treated patients, 33 and 31, respectively, completed the study.

Figure 2

Change in glycemic and inflammatory markers at study end. Data for PI/I ratio (A), A1C (B), C-reactive protein (C), and IL-6 (D) at baseline and end of study (week 52) in patients treated with anakinra (■) or placebo (□) from baseline until week 13. Data are means ± SEM.

Figure 3

IL-1Ra serum levels and genotypes; A1C and insulin requirements. A: Serum IL-1Ra levels at baseline and end of study (week 52) in patients with (□, responders) or without (■, nonresponders) any reduction in A1C after 13 weeks of anakinra treatment. B: Allele frequencies of allele 2 and C of the VNTR tandem repeat polymorphism in intron 2 and the SNP tagged by rs4251961, respectively, of the IL1-Ra gene in responders (□) and nonresponders (■) to anakinra treatment. C: A1C at baseline (week 0), and 13, 26, 39, and 52 weeks in responders (□) and nonresponders (▲) to anakinra treatment. D: Daily insulin dose at baseline and end of study (week 52) in responders (□) and nonresponders (■) to anakinra treatment. Data are means ± SEM or frequencies where indicated.

Figure 4

β-Cell function after anakinra withdrawal. β-Cell function assessed by PI/I (A); and AUC for C-peptide during an oral glucose-tolerance test (B); an intravenous stimulation with glucose, glucagon, and arginine (C); and the oral and intravenous test combined (D) at baseline, anakinra withdrawal (week 13), and end of study (week 52) in patients with (□, responders) or without (■, nonresponders) any reduction in A1C after 13 weeks of anakinra treatment. A: *P = 0.041 vs. nonresponders at week 13, †P = 0.435 vs. responders week 52, ‡P = 0.016 vs. nonresponders week 52, and §P = 0.005 vs. nonresponders week 52. B: *P = 0.006 vs. nonresponders at week 13, †P = 0.750 vs. responders week 52, ‡P = 0.021 vs. nonresponders week 52, and §P = 0.008 vs. nonresponders week 52. C: *P = 0.048 vs. nonresponders at week 13, †P = 0.039 vs. responders week 52, ‡P = 0.793 vs. nonresponders week 52, and §P = 0.092 vs. nonresponders week 52. D: *P = 0.025 vs. nonresponders at week 13, †P = 0.947 vs. responders week 52, ‡P = 0.021 vs. nonresponders week 52, and §P = 0.001 vs. nonresponders week 52. Data are means ± SEM.