Wiley Open Access, CPT: Pharmacometrics and Systems Pharmacology, 6(3), p. 118, 2014
DOI: 10.1038/psp.2014.16
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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.