Six-tissue microphysiological system reveals distinct metabolic and transcriptional responses to metformin and semaglutide

Effective glucose regulation relies on intricate communication between metabolically specialized organs like the gut, pancreas, liver, fat, muscle, and brain. Traditional in vitro models often fail to capture this complex inter-organ crosstalk, limiting our understanding of systemic metabolic diseases like Type 2 Diabetes Mellitus (T2DM) and the mechanisms of anti-diabetic drugs. Current standard-of-care treatments, while effective, often have pleiotropic effects that are difficult to dissect in isolated systems. A comprehensive human multi-tissue platform is crucial to model these interactions and identify novel therapeutic targets or drug response modes.

Researchers developed a perfused human six-tissue microphysiological system (MPS) using the AnthroHive recirculating platform and MOTIVE-6 vessel. This system co-cultured human gut epithelium, pancreatic islets, liver organoids, adipocytes, skeletal muscle, and midbrain-patterned brain organoids. They first benchmarked the system, observing that shared perfusion redirected tissue states towards aligned metabolic, endocrine, absorptive, contractile, and neural programs, while reducing isolation-associated stress. The MPS was then exposed to graded nutrient conditions (Low, Mid, High) to establish a metabolic trajectory. Finally, under High nutrient conditions, the system was treated with metformin and semaglutide to investigate distinct drug response modes, using transcriptomic, metabolomic, functional, endocrine, and inflammatory datasets.

The six-tissue MPS successfully established tissue-aligned metabolic and functional programs under shared perfusion, reducing stress signatures. However, under High nutrient conditions, multi-tissue interaction shifted liver and islet responses toward inflammatory and nutrient-stress-associated gene expression. Graded nutrient exposure revealed a staged circuit trajectory: Low nutrient conditions supported maintenance programs, Mid nutrient exposure induced compensatory endocrine and anabolic remodeling with declining net glucose depletion, and High nutrient exposure shifted the system toward stress-associated metabolic dysfunction. Under these High nutrient conditions, metformin and semaglutide produced distinct response modes. Metformin preserved circuit-level glucose handling without increasing insulin or C-peptide accumulation. > Semaglutide, conversely, extensively remodeled gut, brain organoid, islet, and liver organoid transcriptional programs linked to nutrient sensing, epithelial maintenance, endocrine signaling, and neurometabolic state.