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

ZJ Franklin, A Tsakmaki, Pedro P Fonseca, AJ King, GC Huang, Sakeena Amjad, Shanta J. Persaud, Gavin A. Bewick

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Aims
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.

Results
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.

Conclusion
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
JournalDiabetes, Obesity & Metabolism
Volume20
Issue number3
Early online date22 Sep 2017
DOIs
Publication statusPublished - Mar 2018

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