An Updated Organ-Based Multi-Level Model for Glucose Homeostasis: Organ Distributions, Timing, and Impact of Blood Flow.

Glucose homeostasis is the tight control of glucose in the blood. This complex control is important, due to its malfunction in serious diseases like diabetes, and not yet sufficiently understood. Due to the involvement of numerous organs and sub-systems, each with their own intra-cellular control, we have developed a multi-level mathematical model, for glucose homeostasis, which integrates a variety of data. Over the last 10 years, this model has been used to insert new insights from the intra-cellular level into the larger whole-body perspective. However, the original cell-organ-body translation has during these years never been updated, despite several critical shortcomings, which also have not been resolved by other modelling efforts. For this reason, we here present an updated multi-level model. This model provides a more accurate sub-division of how much glucose is being taken up by the different organs. Unlike the original model, we now also account for the different dynamics seen in the different organs. The new model also incorporates the central impact of blood flow on insulin-stimulated glucose uptake. Each new improvement is clear upon visual inspection, and they are also supported by statistical tests. The final multi-level model describes >300 data points in >40 time-series and dose-response curves, resulting from a large variety of perturbations, describing both intra-cellular processes, organ fluxes, and whole-body meal responses. We hope that this model will serve as an improved basis for future data integration, useful for research and drug developments within diabetes.