Y35 - Reconstructing Human Glucose Regulation In Vitro via Multi-Organ Microphysiological System

Introduction: : Human systemic metabolism is governed by tightly regulated communication among multiple organ systems, including the intestine, liver, pancreas, skeletal muscle, adipose tissue, and brain. These tissues coordinate to maintain glucose homeostasis, lipid balance, and energy allocation in response to nutrient availability and hormonal cues. However, traditional in vitro and animal models often fail to replicate this complex human physiology, contributing to poor translational success in metabolic drug development. To address this challenge, we developed a multiorgan human microphysiological system (MPS) that integrates six key metabolic tissues into a perfused, macrofluidic platform capable of modeling systemic glucose metabolism and pharmacologic responses in vitro.

Materials and

Methods: : Tissue-specific compartments were engineered using 3D cell cultures derived from human primary or stem cell sources, including intestinal epithelium, hepatocyte-rich liver organoids, pancreatic islets, differentiated myotube and adipocyte monolayers, and a brain module. These compartments were linked via a recirculating macrofluidic peristaltic circuit designed to support interorgan signaling through continuous media exchange under various physiologically relevant flow environments. The system was perturbed with nutritional challenges (e.g., fasting and high-fat, high-glucose conditions) and antidiabetic therapeutics (metformin and semaglutide). Functional outputs were measured using morphological analysis, multiplexed hormone assays, as well as transcriptional and metabolomic profiling.

Results, Conclusions, and Discussions:: The integrated multi-organ MPS exhibited coordinated metabolic responses across six human tissue types, including insulin-stimulated glucose uptake, hepatic lipid processing, and secretion of adipokines and incretins. Exposure to pharmacologic agents such as metformin and semaglutide produced physiologically relevant shifts in glucose and lipid dynamics, validating the platform’s predictive potential. System optimizations in flow design, media compatibility, and tissue viability supported stable performance over multiple days and enabled scalability for future parallelized studies. This modular, perfused platform effectively models systemic human metabolism by emulating dynamic interorgan communication under controlled flow conditions. Cross-tissue feedback loops, including hormonal, paracrine, and nutrient-driven signaling, are preserved, allowing for interrogation of complex regulatory mechanisms central to metabolic health and disease. A core strength of this system is its adaptability. The modular design supports tissue-specific tuning, integration of additional organ compartments, and flexible reconfiguration based on research needs. Human-derived cells provide translational relevance, while compatibility with multiplexed biomarker assays and multi-omic profiling enables deep phenotyping and systems-level analysis. As we refine the platform for chronic culture, real-time monitoring, and disease modeling, it offers a powerful tool for investigating metabolic disorders such as type 2 diabetes, NAFLD, and obesity-related inflammation. Ultimately, this MPS serves as a versatile foundation for translational metabolic research, drug development, and the advancement of personalized therapeutic strategies.

Acknowledgements and/or References (Optional)::