The Padova Type 2 Diabetes Simulator from Triple-Tracer Single-Meal Studies: In Silico Trials Also Possible in Rare but Not-So-Rare Individuals

Background: In silico trials in type 2 diabetes (T2D) would be useful for testing diabetes treatments and accelerating the development of new antidiabetic drugs. In this study, we present a T2D simulator able to reproduce the variability observed in a T2D population. The simulator also allows to safely experiment on virtual subjects with severe (and possibly rare) pathological conditions. Methods: A meal simulation model of glucose, insulin, and C-peptide systems, made of 15 differential equations and 39 parameters, has been identified using a system decomposition and forcing function Bayesian strategy on data of 51 T2D subjects undergoing a single triple-tracer mixed meal. One hundred T2D in silico subjects have been generated from the joint distribution of estimated model parameters. A case study is presented to illustrate the simulator use for testing a virtual drug (improving insulin action and secretion) in a subpopulation of rare, extremely impaired, T2D subjects. Results: The model well fitted T2D data and parameters were estimated with precision. Simulated plasma glucose, insulin, and C-peptide well matched the data (e.g., median [25th-75th percentile] glucose area under the curves of 6.9 [6.1-8.5] 104 mg/dL·min in silico vs. 7.0 [5.6-8.2] 104 mg/dL·min in vivo). The potential use of the simulator was shown in a case study, in which the (virtual) antidiabetic drug dose was optimized for very insulin-resistant T2D subjects. Conclusions: We have developed a T2D simulator that captures the behavior of T2D population during a meal, both in terms of average and intersubject variability. The simulator represents a cost-effective way to test new antidiabetic drugs, before moving to human trials.