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CPT Pharmacometrics Syst Pharmacol. 2014 Jun 11;3:e118. doi: 10.1038/psp.2014.16.

Effects of IL-1β-Blocking Therapies in Type 2 Diabetes Mellitus: A Quantitative Systems Pharmacology Modeling Approach to Explore Underlying Mechanisms.

Author information

1
Wolfram MathCore AB, Linköping, Sweden.
2
1] Wolfram MathCore AB, Linköping, Sweden [2] Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
3
Department of Clinical Pharmacology, Drug Metabolism, and Pharmacokinetics, MedImmune, Cambridge, UK.
4
Bioscience, Astra Zeneca, Alderley Park, UK.
5
1] Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden [2] Department of Biomedical Engineering, Linköping University, Linköping, Sweden.

Abstract

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.

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