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Type: Journal article
Title: Inhibition of Y1 receptor signaling improves islet transplant outcome
Author: Loh, K.
Shi, Y.
Walters, S.
Bensellam, M.
Lee, K.
Dezaki, K.
Nakata, M.
Ip, C.
Chan, J.
Gurzov, E.
Thomas, H.
Waibel, M.
Cantley, J.
Kay, T.
Yada, T.
Laybutt, D.
Grey, S.
Herzog, H.
Citation: Nature Communications, 2017; 8(1):490-1-490-12
Publisher: Nature Publishing Group
Issue Date: 2017
ISSN: 2041-1723
Statement of
Kim Loh, Yan-Chuan Shi, Stacey Walters, Mohammed Bensellam, Kailun Lee, Katsuya Dezaki, Masanori Nakata, Chi Kin Ip, Jeng Yie Chan, Esteban N. Gurzov, Helen E. Thomas, Michaela Waibel, James Cantley, Thomas W. Kay, Toshihiko Yada, D. Ross Laybutt, Shane T. Grey, Herbert Herzog
Abstract: Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in β-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.
Keywords: Receptors, Neuropeptide Y
Rights: © 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 licenses/by/4.0/.
RMID: 0030084031
DOI: 10.1038/s41467-017-00624-2
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Appears in Collections:Medicine publications

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