PhysioSeq2Seq: A Hybrid Physiological Digital Twin and Sequence-to-Sequence LSTM for Long-Horizon Glucose Forecasting in Type 1 Diabetes

Accurate forecasting of blood glucose concentration is key in the management of Type 1 Diabetes, facilitating early detection of adverse glycemic events and supporting timely therapeutic interventions. Despite recent advances in glucose prediction, most existing approaches rely on population-level representations or implicit personalization strategies that fail to deliver effective subject-specific forecasts. In this work, we propose Subject-Conditioned Glucose Prediction (SCGP), a novel multimodal deep learning architecture conceived for personalized blood glucose prediction. SCGP conditions glucose predictions based on observed glucose data and a compact subject-specific representation learned from contextual information. By explicitly separating subject characterization from glucose dynamics modeling and avoiding early fusion of heterogeneous inputs, the proposed framework effectively captures inter-subject variability while preserving robust and reliable temporal modeling. Experiments on two state-of-the-art benchmark datasets demonstrate that SCGP consistently improves forecasting performance, enabling reliable detection of adverse glycemic events across multiple prediction horizons, highlighting the benefits of explicit subject conditioning for personalized diabetes management.

Large Language Models (LLMs) are increasingly being investigated for physiological time-series prediction, yet their effectiveness may depend not only on the model itself, but also on how physiological information is represented and presented at inference time. This study investigates prompt-based general-purpose LLMs for postprandial hyperglycemia and hypoglycemia prediction in individuals with type 1 diabetes. Using the OhioT1DM dataset, we evaluate multiple open-weight LLMs under zero-shot and few-shot inference across prediction horizons of 30, 60, and 90 minutes. The analysis varies both the textual representation of the available physiological information and the amount of information exposed to the model, ranging from glucose observations alone to derived descriptors and additional contextual variables related to insulin, meals, carbohydrates, and physical activity. Performance is compared with conventional patient-specific supervised models and with Gluco-LLM, a language-model-based architecture explicitly adapted to glucose time-series forecasting. Results show a marked task-dependent behavior. Conventional supervised models achieve the strongest performance for hyperglycemia prediction, whereas the best observed prompt-based LLM configurations improve performance for hypoglycemia across all investigated horizons. The effectiveness of prompt-based inference is also strongly influenced by how physiological information is represented, while providing additional contextual information does not lead to a systematic improvement. Overall, these findings highlight physiological information representation as a central design factor in prompt-based LLM approaches to glycemic-event prediction.

Blood glucose forecasting models are foundational for modern diabetes management systems, as reliable short-term predictions can enable proactive interventions, support automated insulin delivery, and reduce the risk of hypo- and hyperglycemic events. From a modeling perspective, glucose forecasting poses unique challenges due to heterogeneous physiological dynamics across diabetes populations. Traditional machine learning and deep learning models have been extensively evaluated for glucose prediction, yet recent time-series foundation models (TSFMs) remain much less studied in this setting. To bridge this gap, we present GlucoFM-Bench, a comprehensive benchmark evaluating state-of-the-art TSFMs alongside supervised deep learning models for blood glucose forecasting. We assess eight representative architectures, including pre-trained TSFMs, time-series large language models, and task-specific deep learning models, across 15 publicly available diabetes-relevant datasets comprising 1,117 individuals with type 1 diabetes, type 2 diabetes, prediabetes, and no diabetes. Models are evaluated under zero-shot, few-shot, and full-shot protocols, with systematic variation in context length and prediction horizon. Across datasets, pre-trained TSFMs, especially Chronos-2 and TimesFM, show strong zero-shot and few-shot transfer, with the best zero-shot model performing within 5% of the best full-shot supervised model. Yet, when task-specific data are abundant, a lightweight LSTM remains strongest, outperforming TSFMs by 4--21% under full-shot training. Stratified analyses reveal persistent challenges in T1D cohorts and hypo-/hyperglycemic ranges, highlighting the need for evaluation beyond aggregate error metrics. Together, GlucoFM-Bench provides a standardized and reproducible foundation for evaluating, comparing, and improving foundation models for blood glucose forecasting.