Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2021) 77 P188 | DOI: 10.1530/endoabs.77.P188

SFEBES2021 Poster Presentations Metabolism, Obesity and Diabetes (78 abstracts)

Exploring the translational potential of the NPY Y4 receptor for treating Type 1 Diabetes

Naila Haq 1 , Klaudia Toczyska 1 , Oladapo Olaniru 1 , Patricio Atanes 1 , Annette Beck-Sickinger 2 & Gavin Bewick 1

1Department of Diabetes, King’s College London, London, United Kingdom; 2Leipzig University, Leipzig, Germany

Type 1 diabetes (T1D) is an autoimmune, heterogenous disease caused by immune-mediated destruction of insulin-producing β-cells in the pancreas. The only approved treatment strategies are exogenous insulin replacement therapy and islet transplantation. Leading experimental approaches have focussed on suppression and/or modulation of the immune system. However, efforts to increase β-cell survival are also of great interest. Recent studies in our lab have identified neuropeptide Y (NPY) receptors as novel targets for promoting human β-cell survival. Amongst them, the NP Y4 receptor, has features which make it the most promising NPY receptors candidate for treating T1D. Our Collaborator Prof. Beck-Sickinger, has developed a long-acting synthetic NPY4 receptor agonist K22. This compound has an EC50 of 5.1nM with no or minor potencies for the other NPY receptors. The compound shows excellent in vivo stability in terms of function, bioavailability and is bioactive for 40 hours. We have shown that K22 protects mouse and human islets from multiple toxic insults including cytokines and ER stress and maintains β-cell functionality. Cxcl10 has been identified as a key chemokine driving immune recruitment to islets of T1D patients. We found addition of K22 abolished cytokine induction of Cxcl10 expression and secretion from islets. Using a chemokine profiling assay enabled us to identify a set of immune related genes that are associated with cytotoxic damage of islets, and which are attenuated by K22. Previous studies have shown activation of M1 macrophages is an important initiating step in the pathogenesis of T1D. We modelled this using a pseudo-islet platform generated from murine and human islets. This permitted us to study macrophage infiltration of islets in vitro using an invasion assay and we found K22 completely prevented islet macrophage invasion. Together our data suggests that K22 has important therapeutic potential for delaying T1D disease onset or halting the disease progression.

Volume 77

Society for Endocrinology BES 2021

Edinburgh, United Kingdom
08 Nov 2021 - 10 Nov 2021

Society for Endocrinology 

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