AUTHOR=Lafferty Ryan A. , Tanday Neil , Moffett R. Charlotte , Reimann Frank , Gribble Fiona M. , Flatt Peter R. , Irwin Nigel 

TITLE=Positive Effects of NPY1 Receptor Activation on Islet Structure Are Driven by Pancreatic Alpha- and Beta-Cell Transdifferentiation in Diabetic Mice

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.633625

DOI=10.3389/fendo.2021.633625

ISSN=1664-2392

ABSTRACT=<p>Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic <italic>Glu<sup>CreERT2</sup></italic>;<italic>ROSA26-eYFP</italic> and <italic>Ins1</italic><sup>Cre/+</sup>;<italic>Rosa26-eYFP</italic> mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in <italic>Ins1</italic><sup>Cre/+</sup>;<italic>Rosa26-eYFP</italic> mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p &lt; 0.05 - p &lt; 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both <italic>Glu<sup>CreERT2</sup></italic>;<italic>ROSA26-eYFP</italic> and <italic>Ins1</italic><sup>Cre/+</sup>; <italic>Rosa26-eYFP</italic> mice, STZ provoked characteristic losses (p &lt; 0.05 - p &lt; 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p &lt; 0.001) alpha- to beta-cell transition in <italic>Glu<sup>CreERT2</sup></italic>;<italic>ROSA26-eYFP</italic> mice, together with increased loss of beta-cell identity in <italic>Ins1</italic><sup>Cre/+</sup>;<italic>Rosa26-eYFP</italic> mice, but both effects were significantly (p &lt; 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p &lt; 0.05) beta- to alpha-cell conversion in <italic>Ins1</italic><sup>Cre/+</sup>;<italic>Rosa26-eYFP</italic> mice and glucagon expressing alpha-cells in <italic>Glu<sup>CreERT2</sup></italic>;<italic>ROSA26-eYFP</italic> mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells.</p>