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. 2017 Sep 8;8:490. doi: 10.1038/s41467-017-00624-2

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© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — Improved human islet transplant outcomes due to Y1 receptor antagonism. a Human islets from three independent donors were isolated and cultured for 48 h. Insulin secretion from human islets was determined in response to 2.8 and 28 mM glucose with or without 1 μM BIBO3304 (n = 3; triplicate; three independent donors). b, c Alloxan-induced NOD RAG1^−/− diabetic mice were transplanted with human islets (IEQ 1400) and subsequently orally treated with or without 0.5 μM BIBO3304 and blood glucose levels were monitored for 15 days after which survival nephrectomy was performed (n = 7 per group; two independent donors). Results are also expressed as area under the curve. d, e Human islet recipient mice treated with placebo or 0.5 μM BIBO3304 for 7 days (n = 4) were fasted for 6 h and i.p. glucose tolerance tests (1 g/kg body weight) were performed. Results were also expressed as area under the curve. f Serum insulin levels in human islet recipient mice were determined at day 15 post-transplantation (n = 7). g Alloxan-induced diabetic mice were transplanted with a full MHC mismatch (BALB/c islet −> C57BL/6) optimal number of allogeneic islets (300) (n = 6) or 60 allogeneic islets (n = 14) and treated daily with either 0.5 μM BIBO3304 (n = 6) or placebo (n = 8). h 6-week-old female NOD mice were treated with placebo or 0.5 μM BIBO3304 daily and glucose levels monitored weekly (n = 16 per group). i When the blood glucose levels in BIBO3304-treated mice eventually also reached 12 mM, a 10-fold higher dose of BIBO3304 was given in an attempt to reverse the hyperglycemia (n = 3). j, k, l Glucose tolerance tests were performed in BIBO3304-treated and placebo-treated NOD mice at 11, 15, and 19 weeks of age, respectively (n = 6 per group). m Results were also expressed as area under the curve. n, o Insulitis was scored on islets from NOD mice either treated with 0.5 μM BIBO3304 or placebo at 12 or 22 weeks of age (n = 6, n = 5), respectively. Data are means ± s.e.m. *P < 0.05, **P < 0.01; ***P < 0.001 calculated by t-test (a, c, e, f) or two-way ANOVA analysis