Fig. 1

Paper overview. A The different physiological effects of insulin resistance on glucose homeostasis. B Schematic overview of the multi-level and multi-scale model structure, connecting multiple body levels and timescales. The new reactions (solid lines) include a connection from the Body composition model on the whole-body level to the Meal response model on the organ/tissue level, and the intracellular level, as well as arrows to and from the new insulin resistance model. Reactions in previously published models are shown as dashed lines. C Schematic overview of the analyses made herein, involving two different studies: a weight gain study—the Fast-food study—that was conducted during 12 weeks, and a weight decrease study on the drug topiramate—the Topiramate study. Fast food study: on the whole-body level, the model was trained on weight data as well as fat mass and fat-free mass data, and validated on fat mass and fat free mass, as shown in detail in Fig. 3b, c and Fig. 3c respectively. A prediction of further weight increase was also made, shown in Fig. 4a. On the organ/tissue level, the model was validated on fasting insulin data, shown in Fig. 3d, and predictions were made of meal response insulin, glucose, and glucose uptake in fat and muscle tissue before and after the diet, as shown in Fig. 4b. D Topiramate study: on the whole-body level, the model was trained and validated on weight data for placebo and 3 different dosages of Topiramate. The model was then used to predict two other scenarios not explored in the study—an increase in energy intake with and without medication—as well as meal responses before and after these scenarios, on both organ/tissue and cell level