{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:47:18Z","timestamp":1753879638917,"version":"3.41.2"},"reference-count":19,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,7,28]],"date-time":"2018-07-28T00:00:00Z","timestamp":1532736000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Allogeneic islet transplantation for the treatment of type 1 diabetes often requires multiple implant procedures, from as many as several human pancreas donors, to achieve lasting clinical benefit. Given the limited availability of human pancreases for islet isolation, porcine islets have long been considered a potential option for clinical use. Agarose\u2010encapsulated porcine islets (macrobeads) permit long\u2010term culture and thus a thorough evaluation of microbiological safety and daily insulin secretory capacity, prior to implantation. The goal of this study was the development of a method for determining an effective dose of encapsulated islets based on their measured in vitro insulin secretion in a preclinical model of type 1 diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Spontaneously diabetic BioBreeding diabetes\u2010prone rats were implanted with osmotic insulin pumps in combination with continuous glucose monitoring to establish the daily insulin dose required to achieve continuous euglycaemia in individual animals. Rats were then implanted with a 1\u00d7, 2\u00d7 or 3\u00d7 dose (defined as the ratio of macrobead in vitro insulin secretion per 24\u00a0hours to the recipient animal's total daily insulin requirement) of porcine islet macrobeads, in the absence of immunosuppression. In vivo macrobead function was assessed by recipient non\u2010fasted morning blood glucose values, continuous glucose monitoring and the presence of peritoneal porcine C\u2010peptide. At the end of the study, the implanted macrobeads were removed and returned to in vitro culture for the evaluation of insulin secretion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Diabetic rats receiving a 2\u00d7 macrobead implant exhibited significantly improved blood glucose regulation compared to that of rats receiving a 1\u00d7 dose during a 30\u2010day pilot study. In a 3\u2010month follow\u2010up study, 2\u00d7 and 3\u00d7 macrobead doses initially controlled blood glucose levels equally well, although several animals receiving a 3\u00d7 dose maintained euglycaemia throughout the study, compared to none of the 2\u00d7 animals. The presence of porcine C\u2010peptide in rat peritoneal fluid 3\u00a0months post\u2010implant and the recurrence of hyperglycaemia following macrobead removal, along with the finding of persistent in vitro insulin secretion from retrieved macrobeads, confirmed long\u2010term graft function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Increasing dosages of islet macrobeads transplanted into diabetic rats, based on multiples of in vitro insulin secretion matched to the recipient's exogenous insulin requirements, correlated with improved blood glucose regulation and increased duration of graft function. These results demonstrate the usefulness of a standardized model for the evaluation of the functional effectiveness of islets intended for transplantation, in this case using intraperitoneally implanted agarose macrobeads, in diabetic rats. The results suggest that some features of this islet\u2010dosing methodology may be applicable, and indeed necessary, to clinical allogeneic and xenogeneic islet transplantation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/xen.12443","type":"journal-article","created":{"date-parts":[[2018,7,28]],"date-time":"2018-07-28T18:37:06Z","timestamp":1532803026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A model for determining an effective in vivo dose of transplanted islets based on in vitro insulin secretion"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7907-0866","authenticated-orcid":false,"given":"Robert W.","family":"Holdcraft","sequence":"first","affiliation":[{"name":"Xenia Division The Rogosin Institute  Xenia Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradeep R.","family":"Dumpala","sequence":"additional","affiliation":[{"name":"Xenia Division The Rogosin Institute  Xenia Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry H.","family":"Smith","sequence":"additional","affiliation":[{"name":"The Rogosin Institute  New York New York"},{"name":"NewYork Presbyterian \u2010 Weill Cornell Medical Center  New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence S.","family":"Gazda","sequence":"additional","affiliation":[{"name":"Xenia Division The Rogosin Institute  Xenia 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