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


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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    ABSTRACT: Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed " adipokines. " Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1í µí»½, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled " low-grade inflammatory state " of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.
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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. "

    Full-text · Article · Jan 2015
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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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    ABSTRACT: Non-alcoholic fatty liver disease is prevalent in human obesity and type 2 diabetes, and is characterized by increases in both hepatic triglyceride accumulation (denoted as steatosis) and expression of pro-inflammatory cytokines such as IL-1β. We report here that the development of hepatic steatosis requires IL-1 signaling, which upregulates Fatty acid synthase to promote hepatic lipogenesis. Using clodronate liposomes to selectively deplete liver Kupffer cells in ob/ob mice, we observed remarkable amelioration of obesity-induced hepatic steatosis and reductions in liver weight, triglyceride content and lipogenic enzyme expressions. Similar results were obtained with diet-induced obese mice, although visceral adipose tissue macrophage depletion also occurred in response to clodronate liposomes in this model. There were no differences in the food intake, whole body metabolic parameters, serum β-hydroxybutyrate levels or lipid profiles due to clodronate-treatment, but hepatic cytokine gene expressions including IL-1β were decreased. Conversely, treatment of primary mouse hepatocytes with IL-1β significantly increased triglyceride accumulation and Fatty acid synthase expression. Furthermore, the administration of IL-1 receptor antagonist to obese mice markedly reduced obesity-induced steatosis and hepatic lipogenic gene expression. Collectively, our findings suggest that IL-1β signaling upregulates hepatic lipogenesis in obesity, and is essential for the induction of pathogenic hepatic steatosis in obese mice.
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