Effects of IL-1?-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-1? (IL-1?)-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-1? effects on ?-cell function and turnover with a disease progression model of the long-term interactions between insulin, glucose, and ?-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 ?-cell function, and hence also in HbA1C, fasting plasma glucose, and proinsulin-insulin ratio, and a small increase in ?-cell mass. We propose that improved ?-cell function, rather than mass, is likely to explain the main IL-1?-blocking effects seen in current clinical data, but that improved ?-cell mass might result in disease-modifying effects not clearly distinguishable until >1 year after treatment.

SUBMITTER: Palmer R 

PROVIDER: S-EPMC4076803 | biostudies-other | 2014

REPOSITORIES: biostudies-other