1. Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus
- Author
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Mihai G. Netea, Leo A. B. Joosten, J.W.M. van der Meer, B.J. Kullberg, Cees J. Tack, and G R C Zilverschoon
- Subjects
Adult ,Lipopolysaccharides ,Male ,medicine.medical_specialty ,Staphylococcus aureus ,Health aging / healthy living [IGMD 5] ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Stimulation ,Vascular medicine and diabetes [UMCN 2.2] ,Type 2 diabetes ,Auto-immunity, transplantation and immunotherapy [N4i 4] ,Monocytes ,Invasive mycoses and compromised host [N4i 2] ,Interferon-gamma ,Insulin resistance ,Thinness ,Internal medicine ,Diabetes mellitus ,Candida albicans ,Perception and Action [DCN 1] ,medicine ,Hyperinsulinemia ,Humans ,Obesity ,Cells, Cultured ,Chronic inflammation and autoimmunity [UMCN 4.2] ,Nutrition and Dietetics ,business.industry ,Interleukin-18 ,Type 2 Diabetes Mellitus ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Pathogenesis and modulation of inflammation [N4i 1] ,Endocrinology ,Diabetes Mellitus, Type 2 ,Interleukin 18 ,Female ,Microbial pathogenesis and host defense [UMCN 4.1] ,business ,Infection and autoimmunity [NCMLS 1] ,Immunity, infection and tissue repair [NCMLS 1] - Abstract
Contains fulltext : 69672.pdf (Publisher’s version ) (Closed access) 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-gamma (IFN gamma) production. The defective response to IL-18 stimulation was accompanied by a 50% reduction in the expression of IL-18R alpha and beta chains. In addition, cells of patients with obesity and diabetes displayed an impaired release of IFN gamma 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.
- Published
- 2008