A multi-scale in silico mouse model for insulin resistance and humanoid type 2 diabetes

Abstract

Insulin resistance (IR) causes compensatory insulin production, which in humans eventually progresses to beta-cell failure and type 2 diabetes (T2D). This disease progression involves multi-scale processes, ranging from intracellular signaling to organ-organ and whole-body level regulations, on timescales from minutes to years. T2D progression is commonly studied using overfed and genetically modified rodents. However, rodents do not exhibit human T2D progression, with IR-driven beta-cell failure, and available multi-scale data is too complex to fully comprehend using traditional analysis. To help resolve these issues, we here present an in silico mouse model. This is the first mathematical model that simultaneously explains multi-scale mouse IR data on all three levels – cells, organs, body – ranging from minutes to months. The model correctly predicts new independent multi-scale validation data and provides insights into non-measured processes. Finally, we present a humanoid in silico mouse exhibiting disease progression from IR to IR-driven T2D.

A multi-scale digital twin for adiposity-driven insulin resistance in humans: diet and drug effects

“…Apart from this lack of mechanistic detail, the current implementation of insulin resistance progression is given by a logarithmic expression (Eq. [3][4][5][10][11][12]. This expression thus excludes potential transient and/or adjustment processes in the body.…”

“…The insulin resistance part of the model is inspired by the similar insulin resistance equations implemented for mice in (11). The equations used herein are:…”

“…The multi-level model (Fig. 2) is comprised of three interconnected models, previously published on their own, plus a new insulin resistance model adopted from rodents (11). Firstly, the whole-body model describes changes on body-composition (3), which produces input to the new sub-model for the progression of insulin resistance.…”

“…The insulin resistance model (Fig. 2A, green box) is, as in (11), driven by adiposity, specifically the relative increase in fat mass from baseline (…”

“…This is the first such human, multiscale insulin resistance model. The connecting kit, the adiposity-driven insulin resistance model, has been adopted from a corresponding multi-scale model for mice (11), even though the three constituent models for the three levels and timescales, come from existing models that were specific to humans. Moreover, the cell level model has also been adjusted to allow a continuous development of insulin resistance, by allowing some of the model's steady states to instead change over time.…”