A Physiologically-Constrained Neural Network Digital Twin Framework for Replicating Glucose Dynamics in Type 1 Diabetes

Simulating glucose dynamics in individuals with type 1 diabetes (T1D) is critical for developing personalized treatments and supporting data-driven clinical decisions. Existing models often miss key physiological aspects and are difficult to individualize. Here, we introduce physiologically-constrained neural network (NN) digital twins to simulate glucose dynamics in T1D. To ensure interpretability and physiological consistency, we first build a population-level NN state-space model aligned with a set of ordinary differential equations (ODEs) describing glucose regulation. This model is formally verified to conform to known T1D dynamics. Digital twins are then created by augmenting the population model with individual-specific models, which include personal data, such as glucose management and contextual information, capturing both inter- and intra-individual variability. We validate our approach using real-world data from the T1D Exercise Initiative study. Two weeks of data per participant were split into 5-hour sequences and simulated glucose profiles were compared to observed ones. Clinically relevant outcomes were used to assess similarity via paired equivalence t-tests with predefined clinical equivalence margins. Across 394 digital twins, glucose outcomes were equivalent between simulated and observed data: time in range (70-180 mg/dL) was 75.1±21.2% (simulated) vs. 74.4±15.4% (real; P<0.001); time below range (<70 mg/dL) 2.5±5.2% vs. 3.0±3.3% (P=0.022); and time above range (>180 mg/dL) 22.4±22.0% vs. 22.6±15.9% (P<0.001). Our framework can incorporate unmodeled factors like sleep and activity while preserving key dynamics. This approach enables personalized in silico testing of treatments, supports insulin optimization, and integrates physics-based and data-driven modeling. Code: https://github.com/mosqueralopez/T1DSimAI