Original Article
International Journal of Obesity (2008) 32, 1407–1414; doi:10.1038/ijo.2008.109; published online 22 July 2008
Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus
G R C Zilverschoon1,2, C J Tack1, L A B Joosten1,2,3, B J Kullberg1,2, J W M van der Meer1,2 and M G Netea1,2
- 1Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- 2Radboud University Nijmegen Center for Infectious Diseases, Nijmegen, The Netherlands
- 3Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Correspondence: Dr MG Netea, Department of Medicine (463), Radboud University Nijmegen Medical Center, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands. E-mail: m.netea@aig.umcn.nl
Received 19 March 2008; Revised 5 June 2008; Accepted 12 June 2008; Published online 22 July 2008.
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-
(IFN) production. The defective response to IL-18 stimulation was accompanied by a 50% reduction in the expression of IL-18R 
and 
chains. In addition, cells of patients with obesity and diabetes displayed an impaired release of IFN 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.
Keywords:
Interleukin-18, type 2 diabetes, cytokine
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