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Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus

International Journal of Obesity volume 32, pages 1407–1414 (2008)Cite this article

Abstract

Objective:

Interleukin-18 (IL-18) has been recently demonstrated to improve experimental hyperphagia and insulin resistance. Paradoxically, concentrations of circulating IL-18 in obese subjects and in patients with type 2 diabetes are increased. The objective of this study is to provide an explanation for this paradox.

Design:

We have hypothesized that cells from obese individuals or from patients with type 2 diabetes mellitus have a diminished response to stimulation with IL-18. IL-18 responsiveness was tested by stimulating blood monocytes of obese or diabetes patients with rIL-18 or microbial components.

Results:

Obese individuals and patients with type 2 diabetes mellitus exhibit increased circulating concentrations of IL-18. More importantly, leukocytes isolated from obese or type 2 diabetes patients respond poorly after stimulation with IL-18, as reflected by defective interferon-γ (IFNγ) production. The defective response to IL-18 stimulation was accompanied by a 50% reduction in the expression of IL-18R α and β chains. In addition, cells of patients with obesity and diabetes displayed an impaired release of IFNγ after challenge with bacterial or fungal pathogens, which was due to defective IL-18-mediated signaling.

Conclusion:

Patients with obesity or type 2 diabetes mellitus are characterized by lower responses after stimulation with IL-18. This IL-18 resistance explains the association of obesity and diabetes with high IL-18 circulating concentrations, similar to hyperinsulinemia and hyperleptinemia. IL-18 resistance may represent an important mechanism of the increased susceptibility of these patients to a number of infections.

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Acknowledgements

MGN was supported by a Vidi-grant of the Netherlands Organization for Scientific Research. The research in this paper was partly funded by a grant from the Dutch Diabetes Research Foundation. CJT was partly funded by NIDDK, DK069881.

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Authors and Affiliations

  1. Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    G R C Zilverschoon, C J Tack, L A B Joosten, B J Kullberg, J W M van der Meer & M G Netea

  2. Radboud University Nijmegen Center for Infectious Diseases, Nijmegen, The Netherlands

    G R C Zilverschoon, L A B Joosten, B J Kullberg, J W M van der Meer & M G Netea

  3. Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    L A B Joosten

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  1. G R C Zilverschoon
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  4. B J Kullberg
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Correspondence to M G Netea.

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Zilverschoon, G., Tack, C., Joosten, L. et al. Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus. Int J Obes 32, 1407–1414 (2008). https://doi.org/10.1038/ijo.2008.109

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