Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta‐cell mass. Issue 3 (6th November 2017)

• Record Type: Journal Article
• Authors: Franklin, Zara J.; Tsakmaki, Anastasia; Fonseca Pedro, Patricia; King, Aileen J.; Huang, Guo Cai; Amjad, Sakeena; Persaud, Shanta J.; Bewick, Gavin A.
• Is Part Of: Diabetes, obesity & metabolism. Volume 20:Issue 3(2018)
• Page Start: 599
• Page End: 609
• Publication Date: 2017-11-06
• Subjects: apoptosis -- beta‐cell mass -- diabetes -- islets -- neuropeptide Y -- proliferation; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.13119
• Languages: English
• ISSNs: 1462-8902

Abstract

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 [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.