Fig. 2

Detailed overview of the entire multi-level and multi-timescale model structure on the different levels. New reactions, added in this paper, are represented by solid lines, any color, while old reactions are represented with dashed lines. A Whole-body level. The body composition model takes change in energy intake as input, i.e., the difference in energy intake (\(\mathrm{EI}\)) and energy expenditure (\(\mathrm{EE}\)). This difference translates to the outputs: changes in the masses of fat (\(\mathrm{F}\)), lean tissue (\(\mathrm{L})\), and glycogen \((\mathrm{Gly}\)). The total sum of these masses is the body weight (\(\mathrm{BW}\)). The insulin resistance model (green box) takes the change in fat mass (\(\mathrm{xF}\)) as input. B The following factors influence the glucose concentration on the tissue/organ level: the insulin resistance, \(\mathrm{xF}\), the change in lean tissue (\(\mathrm{xL}\)), and \(\mathrm{BW}\). More specifically, insulin resistance (green short arrows) increases endogenous glucose production (\(\mathrm{EGP}\)) and insulin secretion (\(\mathrm{Ipo}\)), and decreases glucose uptake in both muscle (\({\mathrm{U}}_{\mathrm{idm}}\)) and liver tissue (\({\mathrm{U}}_{\mathrm{idl}}\)). Furthermore, \(\mathrm{xL}\) increases \({\mathrm{U}}_{\mathrm{idm}}\), \(\mathrm{xF}\) increases glucose uptake in fat tissue (\({\mathrm{U}}_{\mathrm{idf}}\)), and \(\mathrm{BW}\) increases the rate of appearance of glucose (\(\mathrm{Ra}\)). C Finally, the amount of insulin in fat tissue translates to insulin input on the cell level. More specifically, insulin binds to the insulin receptor (\(\mathrm{IR}\)), causing a signaling cascade that ultimately results in glucose transporter 4 (\(\mathrm{GLUT}4\)) being translocated to the plasma membrane to facilitate glucose transport. The new reactions on the cell level are the protein expressions of \(\mathrm{IR}\) and \(\mathrm{GLUT}4\) (black arrows going to), the effect of insulin resistance on the protein expression of \(\mathrm{IR}\) and \(\mathrm{GLUT}4\) (green arrows), as well as the degradation of \(\mathrm{IR}\) and \(\mathrm{GLUT}4\) (black arrows going out). These new reactions enable a gradual decrease in \(\mathrm{IR}\) and \(\mathrm{GLUT}4\), moving the cell towards diabetes