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Blockade of interleukin 1 in type 1 diabetes mellitus

Abstract

Interleukin 1 (IL-1) is a 17 kDa protein highly conserved through evolution and is a key mediator of inflammation, fever and the acute-phase response. IL-1 has important functions in the innate immune defense against microbes, trauma and stress, and is also an effector molecule involved in tissue destruction and fibrosis. The inhibition of IL-1 action has clinical efficacy in many inflammatory diseases, such as hereditary autoinflammatory disorders, familial hereditary fever, gout, rheumatoid arthritis and type 2 diabetes mellitus (T2DM). The latter is a common metabolic condition caused by insulin resistance and pancreatic β-cell failure, the causes of both of which have inflammatory components. IL-1 signaling has roles in β-cell dysfunction and destruction via the NFκB and mitogen-activated-protein-kinase pathways, leading to endoplasmic reticulum and mitochondrial stress and eventually activating the apoptotic machinery. In addition, IL-1 acts on T-lymphocyte regulation. The modulating effect of IL-1 on the interaction between the innate and adaptive immune systems and the effects of IL-1 on the β-cell point to this molecule being a potential interventional target in autoimmune diabetes mellitus. Genetic or pharmacological abrogation of IL-1 action reduces disease incidence in animal models of type 1 diabetes mellitus (T1DM) and clinical trials have been started to study the feasibility, safety and efficacy of IL-1 therapy in patients with T1DM. Here, we review the rationale for blocking IL-1 in patients with T1DM.

Key Points

  • Interleukin 1 (IL-1), in synergy with tumor necrosis factor and interferon γ, induces apoptosis of pancreatic β-cells

  • In animal models, IL-1 is expressed in the islets early in the development of type 1 diabetes mellitus

  • Inhibition of IL-1 reduces the incidence of type 1 and type 2 diabetes mellitus in animal models

  • Elevated circulating levels of IL-1 act as a biomarker of development of type 1 and type 2 diabetes mellitus

  • IL-1 blockade improves glycemia and β-cell function in patients with type 2 diabetes mellitus

  • Clinical trials with IL-1 antagonists have been initiated in patients with type 1 diabetes mellitus

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Figure 1: The bimodal effects of IL-1 on β-cell function and viability in vitro.
Figure 2: Factors that aggravate proapoptotic JNK MAPK and NFκB signaling in β cells.
Figure 3: Working model for the main pathways signaling β-cell apoptosis.
Figure 4: Forms of IL-1 antagonism.7

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Mandrup-Poulsen, T., Pickersgill, L. & Donath, M. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol 6, 158–166 (2010). https://doi.org/10.1038/nrendo.2009.271

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