{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T05:00:51Z","timestamp":1780117251292,"version":"3.54.0"},"posted":{"date-parts":[[2026,5,27]]},"group-title":"Bioengineering","reference-count":125,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH NIGMS","award":["5R35GM146900"],"award-info":[{"award-number":["5R35GM146900"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Systemic glucose regulation depends on coordinated signaling among metabolically specialized tissues, yet most human\n                  <jats:italic>in vitro<\/jats:italic>\n                  models capture only limited portions of this network. Here, we developed and benchmarked a perfused human six-tissue MPS by combining AnthroHive, a recirculating perfusion platform, with MOTIVE-6, a six-compartment Multiorgan Tissue Interaction Vessel, to culture human gut epithelium, pancreatic islets, liver organoids, adipocytes, skeletal muscle, and midbrain-patterned brain organoids in a microphysiological system. Shared perfusion redirected engineered tissue states toward tissue-aligned metabolic, endocrine, absorptive, contractile, and neural-associated programs while reducing selected isolation-associated stress and remodeling signatures. Under High nutrient conditions, however, multi-tissue interaction shifted liver and islet responses toward inflammatory and nutrient-stress-associated gene expression, indicating context-dependent effects of cross-compartment signaling. Graded nutrient exposure resolved a staged circuit trajectory: Low nutrient conditions supported maintenance-associated 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 High conditions, metformin and semaglutide produced distinct response modes. Metformin preserved circuit-level glucose handling without increasing insulin or C-peptide accumulation, while semaglutide remodeled gut, brain organoid, islet, and liver organoid transcriptional programs linked to nutrient sensing, epithelial maintenance, endocrine signaling, and neurometabolic state. Together, this study establishes a benchmarked human six-tissue MPS resource, paired with tissue-resolved transcriptomic, shared-media metabolomic, functional, endocrine, and inflammatory datasets, for investigating how tissue interaction, nutrient availability, and metabolic therapies reshape glucose-regulatory networks.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"726943v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                  <jats:p>\n                    Created in BioRender. Trapecar, M. (2026)\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/BioRender.com\/a4tl7nv\">https:\/\/BioRender.com\/a4tl7nv<\/jats:ext-link>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.22.726943","type":"posted-content","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:05:22Z","timestamp":1779919522000},"source":"Crossref","is-referenced-by-count":0,"title":["Inter-organ communication shapes human metabolic tissue states and resolves anti-diabetic drug response modes in a six-tissue microphysiological system"],"prefix":"10.64898","author":[{"given":"Marissa","family":"McGilvrey","sequence":"first","affiliation":[{"name":"Institute for Fundamental Biomedical Research, Johns Hopkins All Children\u2019s Hospital, St. Petersburg, FL, USA"},{"name":"Department of Medicine-Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 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