Background and Objective:Patients who underwent Roux-en-Y Gastric Bypass surgery for treatment of obesity or diabetes can suffer from post-bariatric hypoglycemia (PBH). It has been assumed that PBH is caused by increased levels of the hormone GLP-1. In this research, we elucidate the role of GLP-1 in PBH with a physiology-based mathematical model. Methods:The Eindhoven Diabetes Simulator (EDES) model, simulating postprandial glucose homeostasis, was adapted to include the effect of GLP-1 on insulin secretion. Parameter sensitivity analysis was used to identify parameters that could cause PBH. Virtual patient models were created by defining sets of models parameters based on 63 participants from the HypoBaria study cohort, before and one year after bariatric surgery. Results:Simulations with the virtual patient models showed that glycemic excursions can be correctly simulated for the study population, despite heterogeneity in the glucose, insulin and GLP-1 data. Sensitivity analysis showed that GLP-1 stimulated insulin secretion alone was not able to cause PBH. Instead, analyses showed the increased transit speed of the ingested food resulted in quick and increased glucose absorption in the gut after surgery, which in turn induced postprandial glycemic dips. Furthermore, according to the model post-bariatric increased rate of glucose absorption in combination with different levels of insulin sensitivity can result in PBH. Conclusions:Our model findings implicate that if initial rapid improvement in insulin sensitivity after gastric bypass surgery is followed by a more gradual decrease in insulin sensitivity, this may result in the emergence of PBH after prolonged time (months to years after surgery).