Article

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

Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark.
Diabetes care (Impact Factor: 8.42). 07/2009; 32(9):1663-8. DOI: 10.2337/dc09-0533
Source: PubMed

ABSTRACT

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

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    • "The blockade of IL-1 with Anakinra improved glycaemia, í µí»½-cell function, and circulating inflammatory factors in a clinical trial involving 70 patients with type 2 diabetes [110] [116]. This showed that IL-1 blockers could have a high impact in the treatment of obesity-induced inflammation and insulin resistance as well as the treatment of autoimmune diseases, such as type 1 diabetes. "
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    • "Moreover, given that " IL-1 induces IL-1 " through a positive feedback loop that characterizes autoinflammatory diseases; interruption of this feedback may result in sustained anti-inflammatory effects beyond the actual pharmacological half-life of the drug. In a study of patients with diabetes, treatment with anakinra for 13 weeks showed an improvement in pancreatic β-cell function that was maintained at 52 weeks (39 weeks after discontinuation of treatment)[29]. Canakinumab, a monoclonal antibody blocking IL-1β, also lowers CRP levels for longer than the reported 24-day half-life[30]. The design of the RED-HART with prolonged wash-out periods after a short (2 weeks) or longer (12 weeks) treatment will provide data in regards to the duration of the effects after termination of therapy. "

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    • "To confirm that IL-1Ra was biologically active in these mice, we performed intraperitoneal glucose tolerance tests (GTTs) 28 days after the start of injections (Fig. 8B). Consistent with previous studies [20], [21], IL-1Ra treatment improved glucose tolerance without affecting the total animal body weight in DIO mice (Fig. 8; p≤0.05). "
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