2. Academic Validation
  3. Inhibition of Y1 receptor signaling improves islet transplant outcome

Inhibition of Y1 receptor signaling improves islet transplant outcome

  • Nat Commun. 2017 Sep 8;8(1):490. doi: 10.1038/s41467-017-00624-2.
Kim Loh 1 2,  Yan-Chuan Shi 1 3,  Stacey Walters 4,  Mohammed Bensellam 5 6,  Kailun Lee 1,  Katsuya Dezaki 7,  Masanori Nakata 7,  Chi Kin Ip 1,  Jeng Yie Chan 5,  Esteban N Gurzov 2,  Helen E Thomas 2,  Michaela Waibel 2,  James Cantley 5 8,  Thomas W Kay 2,  Toshihiko Yada 7,  D Ross Laybutt 5,  Shane T Grey 9,  Herbert Herzog 10 11
Affiliations

Affiliations

  • 1 Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, 2010, Australia.
  • 2 St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
  • 3 Faculty of Medicine, UNSW Australia, Sydney, NSW, 2052, Australia.
  • 4 Immunology Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, 2010, Australia.
  • 5 Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, 2010, Australia.
  • 6 Institute of Experimental and Clinical Research, Pole of Endocrinology, Diabetes and Nutrition, Université Catholique De Louvain, Brussels, B-1200, Belgium.
  • 7 Department of Physiology, Jichi Medical University, Tochigi, 329-0498, Japan.
  • 8 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
  • 9 Immunology Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, 2010, Australia. s.grey@garvan.org.au.
  • 10 Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, 2010, Australia. h.herzog@garvan.org.au.
  • 11 Faculty of Medicine, UNSW Australia, Sydney, NSW, 2052, Australia. h.herzog@garvan.org.au.
PMID: 28887564 DOI: 10.1038/s41467-017-00624-2
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.

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