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Effects of IL-1β-Blocking Therapies in Type 2 Diabetes Mellitus: A Quantitative Systems Pharmacology Modeling Approach to Explore Underlying Mechanisms
Wolfram MathCore AB, Linköping, Sweden;.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Wolfram MathCore AB, Linköping, Sweden;.
Department of Clinical Pharmacology, Drug Metabolism, and Pharmacokinetics, MedImmune, Cambridge, UK.
Bioscience, Astra Zeneca, Alderley Park, UK.
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2014 (English)In: CPT: pharmacometrics & systems pharmacology, ISSN 2163-8306, Vol. 3, no 6, 1-8 p.Article in journal (Refereed) Published
Abstract [en]

Recent clinical studies suggest sustained treatment effects of interleukin-1β (IL-1β)-blocking therapies in type 2 diabetes mellitus. The underlying mechanisms of these effects, however, remain underexplored. Using a quantitative systems pharmacology modeling approach, we combined ex vivo data of IL-1β effects on β-cell function and turnover with a disease progression model of the long-term interactions between insulin, glucose, and β-cell mass in type 2 diabetes mellitus. We then simulated treatment effects of the IL-1 receptor antagonist anakinra. The result was a substantial and partly sustained symptomatic improvement in β-cell function, and hence also in HbA1C, fasting plasma glucose, and proinsulin-insulin ratio, and a small increase in β-cell mass. We propose that improved β-cell function, rather than mass, is likely to explain the main IL-1β-blocking effects seen in current clinical data, but that improved β-cell mass might result in disease-modifying effects not clearly distinguishable until >1 year after treatment.

Place, publisher, year, edition, pages
2014. Vol. 3, no 6, 1-8 p.
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Bioinformatics and Systems Biology
URN: urn:nbn:se:liu:diva-114549DOI: 10.1038/psp.2014.16PubMedID: 24918743ScopusID: 2-s2.0-84903772139OAI: diva2:791044
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2015-08-10

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