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Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta‐cell mass
Author(s) -
Franklin Zara J.,
Tsakmaki Anastasia,
Fonseca Pedro Patricia,
King Aileen J.,
Huang Guo Cai,
Amjad Sakeena,
Persaud Shanta J.,
Bewick Gavin A.
Publication year - 2018
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13119
Subject(s) - receptor , beta cell , microbiology and biotechnology , biology , islet , neuropeptide y receptor , agonist , endocrinology , signal transduction , beta (programming language) , programmed cell death , medicine , apoptosis , diabetes mellitus , neuropeptide , biochemistry , computer science , programming language
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 [Leu 31 Pro 34 ]‐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.