Inhibition of Y1 receptor signaling improves islet transplant outcome

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 (Lead / Corresponding author), Herbert Herzog (Lead / Corresponding author)

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9 Citations (Scopus)
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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.

Original languageEnglish
Article number490
Number of pages12
JournalNature Communications
Volume8
Issue number1
Early online date8 Sep 2017
DOIs
Publication statusPublished - 1 Dec 2017

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