IngentaConnect Evaluation of proinflammatory cytokines and inflammation markers ...

Authors: van Doorn, Martijn; Kemme, Michiel; Ouwens, Margriet¹; van Hoogdalem, Ewoud J.²; Jones, Richard³; Romijn, Hans⁴; de Kam, Marieke; Schoemaker, Rik; Burggraaf, Koos; Cohen, Adam

Source: British Journal of Clinical Pharmacology, Volume 62, Number 4, October 2006 , pp. 391-402(12)

Publisher: Blackwell Publishing

Abstract:

Aims

Thiazolidinediones (TZDs) not only enhance cellular glucose transport but are reported to have potent anti-inflammatory effects. These effects may play an important role in the insulin sensitizing mechanism, and possibly precede the effects on parameters of glucoregulation. We sought to investigate whether these anti-inflammatory effects could yield early responding biomarkers for TZD action in Type 2 diabetes mellitus (T2DM) patients and healthy volunteers (HV) to expedite early clinical development of novel compounds. Methods

We investigated the timing of treatment effects on several proinflammatory cytokines and markers of inflammation in comparison with effects on typical measures of glucoregulation in T2DM patients and HV receiving rosiglitazone 4 mg or placebo twice daily for 6 weeks. Results

We found a significant reduction in interleukin (IL)-6 [−39.4%, confidence interval (CI) − 60.0, − 8.2] and white blood cell count (−18.4%, CI − 30.2, − 4.5) after 4 weeks of treatment in the T2DM group. These anti-inflammatory effects did not precede the effects on typical parameters of glucoregulation in the T2DM group and there was no significant anti-inflammatory response in the HV group. Conclusion

We could not identify biomarkers that precede the effects of rosiglitazone on parameters of glucoregulation in T2DM or that have a significant response in HV. However, the IL-6 response observed in this study indicates a potential role for this cytokine as complementary biomarker in clinical `proof of concept' studies with novel TZDs.

Document Type: Research article

DOI: 10.1111/j.1365-2125.2005.02532.x

Affiliations: 1: Department of Molecular Biology, Leiden University, Leiden, the Netherlands, 2: Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium, 3: Biopharma-PS, Basel, Switzerland, and 4: Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands

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Evaluation of proinflammatory cytokines and inflammation markers as biomarkers for the action of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers