title: Effects of IL-1β-Blocking Therapies in Type 2 Diabetes Mellitus: A Quantitative Systems Pharmacology Modeling Approach to Explore Underlying Mechanisms.
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.
authors.affiliation: Wolfram MathCore AB, Linköping, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Palmér
authors.affiliation: 1] Wolfram MathCore AB, Linköping, Sweden [2] Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Nyman
authors.affiliation: Department of Clinical Pharmacology, Drug Metabolism, and Pharmacokinetics, MedImmune, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Penney
authors.affiliation: Bioscience, Astra Zeneca, Alderley Park, UK.
authors.forename: A
authors.initials: A
authors.lastname: Marley
authors.affiliation: 1] Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden [2] Department of Biomedical Engineering, Linköping University, Linköping, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Cedersund
authors.affiliation: Department of Clinical Pharmacology, Drug Metabolism, and Pharmacokinetics, MedImmune, Cambridge, UK.
authors.forename: B
authors.initials: B
authors.lastname: Agoram