3 years ago

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

A Tsakmaki, GA Bewick, P Fonseca Pedro, SJ Persaud, GC Huang, AJ King, ZJ Franklin
Objective Two unmet therapeutic strategies for diabetes treatment are prevention of beta-cell death and stimulation of beta-cell replication. Our aim was to characterise the role of Neuropeptide Y receptors in the control of beta-cell mass. 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 validate if targeting this system could preserve beta-cell mass in vivo. Results Our data reveal NPY Y1, 4 and 5 receptor activation engages a generalised and powerful anti-apoptotic pathway which protects mouse and human islets from damage. This 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 2 diabetes and may also be useful for improving islet transplantation outcomes.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/dom.13119

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