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Here, we have connected cell\u00a0models of key metabolic organs, the pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modeling, we demonstrate that hyperglycemia and high cortisone\u00a0concentration induce glucose dysregulation in the pancreas-liver microphysiological system (MPS), mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, the pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. Conversely, a physiological culture condition maintains glucose tolerance and beta-cell function. This method was reproducible in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins, as demonstrated with a combined transcriptome and proteome analysis.<\/jats:p>","DOI":"10.1038\/s42003-024-06514-w","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T04:02:04Z","timestamp":1721275324000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Normoglycemia and physiological cortisone level maintain glucose homeostasis in a pancreas-liver microphysiological system"],"prefix":"10.1038","volume":"7","author":[{"given":"Sophie","family":"Rigal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Casas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajsa P.","family":"Kanebratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Wennberg Huldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa U.","family":"Magnusson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2176-3248","authenticated-orcid":false,"given":"Erik","family":"M\u00fcllers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Clausen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara F.","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Leonard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-1401","authenticated-orcid":false,"given":"Jonathan","family":"Cairns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Jansson L\u00f6fmark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"\u00c4mm\u00e4l\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Marx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7865-7454","authenticated-orcid":false,"given":"Peter","family":"Gennemark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Cedersund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommy B.","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9184-4847","authenticated-orcid":false,"given":"Liisa K.","family":"Vil\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"6514_CR1","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/414799a","volume":"414","author":"AR Saltiel","year":"2001","unstructured":"Saltiel, A. 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