{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:46:29Z","timestamp":1774950389500,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010587","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000}}],"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018-05418, 2018-03319"],"award-info":[{"award-number":["2018-05418, 2018-03319"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CENIIT","award":["15.09"],"award-info":[{"award-number":["15.09"]}]},{"DOI":"10.13039\/501100001729","name":"Stiftelsen f\u00f6r Strategisk Forskning","doi-asserted-by":"publisher","award":["ITM17-0245"],"award-info":[{"award-number":["ITM17-0245"]}],"id":[{"id":"10.13039\/501100001729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009252","name":"Science for Life Laboratory","doi-asserted-by":"publisher","award":["2020.0182"],"award-info":[{"award-number":["2020.0182"]}],"id":[{"id":"10.13039\/501100009252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["777107"],"award-info":[{"award-number":["777107"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009487","name":"Stiftelsen Forska Utan Djurf\u00f6rs\u00f6k","doi-asserted-by":"publisher","award":["F2019-0010"],"award-info":[{"award-number":["F2019-0010"]}],"id":[{"id":"10.13039\/100009487","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ELLIIT","award":["2020-A12"],"award-info":[{"award-number":["2020-A12"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Microphysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression <jats:italic>in vitro<\/jats:italic>. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and <jats:italic>in vivo<\/jats:italic> extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach. This approach allows for <jats:italic>in silico<\/jats:italic> representation and predictions of glucose metabolism in a previously reported MPS with two organ compartments (liver and pancreas) connected in a closed loop with circulating medium. We developed a computational model describing glucose metabolism over 15 days of culture in the MPS. The model was calibrated on an experiment-specific basis using data from seven experiments, where HepaRG single-liver or liver-islet cultures were exposed to both normal and hyperglycemic conditions resembling high blood glucose levels in diabetes. The calibrated models reproduced the fast (i.e. hourly) variations in glucose and insulin observed in the MPS experiments, as well as the long-term (i.e. over weeks) decline in both glucose tolerance and insulin secretion. We also investigated the behaviour of the system under hypoglycemia by simulating this condition <jats:italic>in silico<\/jats:italic>, and the model could correctly predict the glucose and insulin responses measured in new MPS experiments. Last, we used the computational model to translate the experimental results to humans, showing good agreement with published data of the glucose response to a meal in healthy subjects. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010587","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T17:42:28Z","timestamp":1666201348000},"page":"e1010587","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Integrated experimental-computational analysis of a HepaRG liver-islet microphysiological system for human-centric diabetes research"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2479-1751","authenticated-orcid":true,"given":"Bel\u00e9n","family":"Casas","sequence":"first","affiliation":[]},{"given":"Liisa","family":"Vil\u00e9n","sequence":"additional","affiliation":[]},{"given":"Sophie","family":"Bauer","sequence":"additional","affiliation":[]},{"given":"Kajsa P.","family":"Kanebratt","sequence":"additional","affiliation":[]},{"given":"Charlotte","family":"Wennberg Huldt","sequence":"additional","affiliation":[]},{"given":"Lisa","family":"Magnusson","sequence":"additional","affiliation":[]},{"given":"Uwe","family":"Marx","sequence":"additional","affiliation":[]},{"given":"Tommy B.","family":"Andersson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7865-7454","authenticated-orcid":true,"given":"Peter","family":"Gennemark","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9386-0568","authenticated-orcid":true,"given":"Gunnar","family":"Cedersund","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"issue":"6","key":"pcbi.1010587.ref001","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/dmrr.863","article-title":"Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?","volume":"24","author":"FQ Nuttall","year":"2008","journal-title":"Diabetes Metab Res Rev"},{"issue":"12","key":"pcbi.1010587.ref002","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.2337\/diab.38.12.1512","article-title":"Toward physiological understanding of glucose tolerance. 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