Microphysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression in vitro. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and in vivo extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach. This approach allows for in silico representation and predictions of glucose metabolism in a previously reported MPS with two organ compartments (liver and pancreas) connected in a closed loop with circulating medium. We developed a computational model describing glucose metabolism over 15 days of culture in the MPS. The model was calibrated on an experiment-specific basis using data from seven experiments, where HepaRG single-liver or liver-islet cultures were exposed to both normal and hyperglycemic conditions resembling high blood glucose levels in diabetes. The calibrated models reproduced the fast (i.e. hourly) variations in glucose and insulin observed in the MPS experiments, as well as the long-term (i.e. over weeks) decline in both glucose tolerance and insulin secretion. We also investigated the behaviour of the system under hypoglycemia by simulating this condition in silico, and the model could correctly predict the glucose and insulin responses measured in new MPS experiments. Last, we used the computational model to translate the experimental results to humans, showing good agreement with published data of the glucose response to a meal in healthy subjects. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders. Author summary: Microphysiological systems (MPS) are powerful tools to unravel biological knowledge underlying disease. MPS provide a physiologically relevant, human-based in vitro setting, which can potentially yield better translatability to humans than current animal models and traditional cell cultures. However, mechanistic interpretation and extrapolation of the experimental results to human outcome remain significant challenges. In this study, we confront these challenges using an integrated experimental-computational approach. We present a computational model describing glucose metabolism in a previously reported MPS integrating liver and pancreas. This MPS supports a homeostatic feedback loop between HepaRG/HHSteC spheroids and pancreatic islets, and allows for detailed investigations of mechanisms underlying type 2 diabetes in humans. We show that the computational model captures the complex dynamics of glucose-insulin regulation observed in the system, and can provide mechanistic insight into disease progression features, such as insulin resistance and β-cell dynamics. Furthermore, the computational model can explain key differences in temporal dynamics between MPS and human responses, and thus provides a tool for translating experimental insights into human outcome. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders. [ABSTRACT FROM AUTHOR]