Theoretical analysis of insulin‐dependent glucose uptake heterogeneity in 3D bioreactor cell culture

Abstract

Three-dimensional (3D) cell cultures in bioreactors are becoming relevant as models for biological and physiological in vitro studies. In such systems, mathematical models can assist the experiment design that links the macroscopic properties to single-cell responses. We investigated the relationship between biochemical stimuli and cell response within a 3D cell culture in scaffold with heterogeneous porosity. Specifically, we studied the effect of insulin on the local glucose metabolism as a function of 3D pore size distribution. The multiscale mathematical model combines the mass transport within a 3D scaffold and a signaling pathways model. It considers the scaffold heterogeneity, and it describes spatiotemporal concentration of metabolites, biochemical stimuli, and cell density. The signaling model was integrated into this model, linking the local insulin concentration at cell membrane to the glucose uptake rate through glucose transporter type 4 (GLUT4) translocation from the cytosol to the cell membrane. The integrated model determines the cell response heterogeneities in a single channel, hence the biological response distribution in a 3D system. It also provides macroscopic outcomes to evaluate the feasibility of an experimental measurement of the system response. From our analysis, it became apparent that the flow rate is the most important operative variable, and that an optimum value ensures a fast and detectable cell response. This model on insulin-dependent glucose consumption rate offers insight into the cell metabolism physiology, which is a fundamental requirement for the study metabolic disorder such as Type 2 diabetes mellitus, in which the physiological insulin-dependent glucose metabolism is impaired.

High Temporal Resolution Detection of Patient-Specific Glucose Uptake from Human ex Vivo Adipose Tissue On-Chip

“…This cellular uptake was included in the model by describing the insulin signaling pathway, which involves insulin internalization and, after a phosphorylation cascade, glucose entrance into the cells by active transport. Specifically, fluid dynamics was described by the Navier–Stokes equation for incompressible fluids, molecular diffusion by Fick’s law, and glucose and insulin consumption by combining a model of the insulin signaling pathway, reduced as previously described, , with a Michaelis–Menten kinetic model . Results are reported in terms of outlet glucose concentration normalized by the concentration at the inlet.…”

A receptor state space model of the insulin signalling system in glucose transport

“…Mathematical analysis of the Sedaghat model revealed a lack of conservation of IR and stiffness in the equations of the IR subsystem. In at least two recent papers utilising the Sedaghat model (Luni & Doyle (2011);Magrofuoco et al (2012)), the IR subsystem was modified by removing the IR degradation/synthesis terms to make a closed subsystem. Furthermore, the drift in the system to higher numbers of IR under insulin stimulation is counter to experimental results: upregulation of IR numbers occurs in response to long-term insulin withdrawal, rather than insulin stimulation (Puig & Tjian (2005)).…”

The Use of Mathematical Modelling for Improving the Tissue Engineering of Organs and Stem Cell Therapy

“…The nature of the included mechanisms can be diverse and may be chemical e.g. for describing the metabolism of nutrients by cells [27], or physical e.g. to account for fluid shear stress experienced by cells in bioreactors [28].…”