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 () and Herbert Herzog ()
Additional contact information
Kim Loh: St Vincent’s Hospital
Yan-Chuan Shi: St Vincent’s Hospital
Stacey Walters: St Vincent’s Hospital
Mohammed Bensellam: St Vincent’s Hospital
Kailun Lee: St Vincent’s Hospital
Katsuya Dezaki: Jichi Medical University
Masanori Nakata: Jichi Medical University
Chi Kin Ip: St Vincent’s Hospital
Jeng Yie Chan: St Vincent’s Hospital
Esteban N. Gurzov: St. Vincent’s Institute of Medical Research
Helen E. Thomas: St. Vincent’s Institute of Medical Research
Michaela Waibel: St. Vincent’s Institute of Medical Research
James Cantley: St Vincent’s Hospital
Thomas W. Kay: St. Vincent’s Institute of Medical Research
Toshihiko Yada: Jichi Medical University
D. Ross Laybutt: St Vincent’s Hospital
Shane T. Grey: St Vincent’s Hospital
Herbert Herzog: St Vincent’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00624-2

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