Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Department of Biomedical Engineering, Linköping University, Linköping, Sweden.
PLoS Comput Biol. 2022 Oct 19;18(10):e1010587. doi: 10.1371/journal.pcbi.1010587. eCollection 2022 Oct.
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.
微生理系统（MPS）是模拟人体生理学并在体外复制疾病进展的强大工具。MPS 可能比当前的动物模型更好地预测人类的结果，但对实验结果的机制解释和体内外推仍然是重大挑战。在这里，我们使用集成的实验计算方法来应对这些挑战。该方法允许在以前报道的具有两个器官腔（肝和胰腺）的 MPS 中对葡萄糖代谢进行计算机模拟和预测，该腔与循环介质相连形成闭环。我们开发了一个描述 MPS 中培养 15 天的葡萄糖代谢的计算模型。该模型是在特定实验的基础上使用来自七个实验的数据进行校准的，其中 HepaRG 单肝或肝胰岛培养物分别暴露于正常和高血糖条件下，模拟糖尿病中的高血糖水平。校准后的模型再现了 MPS 实验中观察到的葡萄糖和胰岛素的快速（即每小时）变化，以及葡萄糖耐量和胰岛素分泌的长期（即数周）下降。我们还通过计算机模拟研究了系统在低血糖下的行为，模型可以正确预测新的 MPS 实验中测量的葡萄糖和胰岛素反应。最后，我们使用计算模型将实验结果转换为人类，与健康受试者餐后葡萄糖反应的已发表数据吻合良好。集成的实验计算框架为未来对疾病机制的研究和代谢紊乱新疗法的开发开辟了新的途径。
