02463nas a2200361   4500000000100000000000100001008004100002260001500043653004400058653001600102653001800118653002300136653002300159100001700182700002900199700002300228700002000251700001800271700002200289700001600311700002200327700002000349700001800369700002100387700001300408700002300421245013400444856005500578300001000633490000600643520143800649022001402087       2017                            d  c2017-11-0310aEndocrine system and metabolic diseases10aHomeostasis10aLab-on-a-chip10aMetabolic diseases10aTissue engineering1 aSophie Bauer1 aCharlotte Wennberg Huldt1 aKajsa P. Kanebratt1 aIsabell Durieux1 aDaniela Gunne1 aShalini Andersson1 aLorna Ewart1 aWilliam G. Haynes1 aIlka Maschmeyer1 aAnnika Winter1 aCarina Ämmälä1 aUwe Marx1 aTommy B. Andersson00aFunctional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model  uhttps://www.nature.com/articles/s41598-017-14815-w  a146200 v73 aHuman in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet–liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium. Functional coupling, demonstrated by insulin released from the islet microtissues in response to a glucose load applied in glucose tolerance tests on different days, promoted glucose uptake by the liver spheroids. Co-cultures maintained postprandial glucose concentrations in the circulation whereas glucose levels remained elevated in both single cultures. Thus, insulin secreted into the circulation stimulated glucose uptake by the liver spheroids, while the latter, in the absence of insulin, did not consume glucose as efficiently. As the glucose concentration fell, insulin secretion subsided, demonstrating a functional feedback loop between the liver and the insulin-secreting islet microtissues. Finally, inter-laboratory validation verified robustness and reproducibility. Further development of this model using tools inducing impaired glucose regulation should provide a unique in vitro system emulating human type 2 diabetes mellitus.  a2045-2322