Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass.

ZJ Franklin, A Tsakmaki, Patricia Fonseca Pedro, AJ King, GC Huang, Sakeena Amjad, Shanta J. Persaud, Gavin A. Bewick* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Two unmet therapeutic strategies for diabetes treatment are prevention of beta-cell death and stimulation of beta-cell replication. Our aim was to characterize the role of neuropeptide Y receptors in the control of beta-cell mass.

Materials and Methods
We used endogenous and selective agonists of the NPY receptor system to explore its role in the prevention of beta-cell apoptosis and proliferation in islets isolated from both mouse and human donors. We further explored the intra-cellular signalling cascades involved, using chemical inhibitors of key signalling pathways. As proof of principle we designed a long-acting analogue of [Leu31Pro34]-NPY, an agonist of the islet-expressed Y receptors, to determine if targeting this system could preserve beta-cell mass in vivo.

Our data reveal that NPY Y1, 4 and 5 receptor activation engages a generalized and powerful anti-apoptotic pathway that protects mouse and human islets from damage. These anti-apoptotic effects were dependent on stimulating a Gαi-PLC-PKC signalling cascade, which prevented cytokine-induced NFkB signalling. NPY receptor activation functionally protected islets by restoring glucose responsiveness following chemically induced injury in both species. NPY receptor activation attenuated beta-cell apoptosis, preserved functional beta-cell mass and attenuated the hyperglycaemic phenotype in a low-dose streptozotocin model of diabetes.

Taken together, our observations identify the islet Y receptors as promising targets for the preservation of beta-cell mass. As such, targeting these receptors could help to maintain beta-cell mass in both type 1 and type 2 diabetes, and may also be useful for improving islet transplantation outcomes.
Original languageEnglish
Pages (from-to)599-609
Number of pages11
JournalDiabetes, Obesity & Metabolism
Issue number3
Early online date22 Sept 2017
Publication statusPublished - Mar 2018
Externally publishedYes

Bibliographical note

Funding information Work in G. A. B.'s laboratory is funded by a JDRF project grant, 17-2013-417, a National Institute for Health Research (NIHR) career development fellowship, CDF-2011-04-006, and an EFSD Boehringer-Ingleheim project grant.

Data Availability Statement

Additional Supporting Information may be found online in the supporting information tab for this article.


  • apoptosis
  • beta-cell mass
  • diabetes
  • islets
  • neuropeptide Y
  • proliferation


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