Advancing Bihormonal Closed-Loop Systems: The Role of Glucagon in Glucose Management of Diabetes Mellitus Type 1

Introduction In the past decades, there has been a growing interest in incorporating glucagon into continuous subcutaneous insulin infusion therapy for Type 1 Diabetes Mellitus patients. However, widespread adoption as a standard treatment option has not yet been realized. The development of bihormonal closed-loop systems involves investigating the pharmacodynamics of glucagon in controlled settings. While some studies have examined these systems in real-life settings, the focus has primarily been on their overall success in regulating glucose levels within target ranges. Limited information is available on the real-life impact of glucagon on glucose levels. Objectives This study aims to assess the effect of glucagon on glucose levels in real-life data, exploring various conditions and investigating the impact of glucagon settings in the Inreda AP, the first CE-certified bihormonal closed-loop system. The objective is to gain deeper insights into the role of glucagon in glucose management, comprehend glucagon aspects within treatments with the Inreda AP, and explore potential optimizations for enhanced effectiveness. Methods Glucose responses to glucagon are systematically mapped under various conditions, including control (blockage), insulin on board, and different situations (baseline glucose value, rate of glucose change and amount of glucagon) and patient characteristics (gender, age, BMI, diabetes duration, HbA1c, total daily insulin dosages and insulin sensitivity). The impact of alterations in system settings on regulatory outcomes is also examined. Cluster analysis is applied to predict glucagon settings. Conclusions This research demonstrates that, in real-life scenarios, glucagon administration can lead to earlier and more pronounced increases in glucose levels. The presence of insulin on board mitigates glucose excursions after glucagon dosage, yet the pre-dosage rate of glucose change appears to be a more decisive factor. Moreover, patients with lower insulin requirements exhibit greater glucose excursions compared to those with higher insulin needs. Although there is no one-size-fits-all glucagon setting, reducing settings results in decreased individual glucagon usage. Practical recommendations for treatment adjustments and algorithm refinements are derived from this study, offering valuable insights to enhance the effective use of glucagon in glucose regulation.