The Beneficial Impact of a Novel Pancreatic Polypeptide Analogue on Islet Cell Lineage

(Proline3)PP, or (P3
)PP, is an enzymatically stable, neuropeptide Y4 receptor (NPY4R)-selective, pancreatic polypeptide (PP) analogue with established weightlowering and pancreatic islet morphology benefits in obesity-diabetes. In the current study,
we now investigate the impact of twice-daily (P3
)PP administration (25 nmol/kg) for
11 days on islet cell lineage, using streptozotocin (STZ) diabetic Ins1Cre/+;Rosa26-eYFP
and GluCreERT2;Rosa26-eYFP transgenic mice with enhanced yellow fluorescent protein
(eYFP) labelling of beta-cell and alpha-cells, respectively. (P3
)PP had no obvious impact
on body weight or blood glucose levels in STZ-diabetic mice at the dose tested, but did
return food intake towards control levels in Ins1Cre/+;Rosa26-eYFP mice. Notably, pancreatic
insulin content was augmented by (P3
)PP treatment in both Ins1Cre/+;Rosa26-eYFP and
GluCreERT2;Rosa26-eYFP mice, alongside enhanced beta-cell area and reduced alpha-cell
area. Beneficial (P3
)PP-induced changes on islet morphology were consistently associated
with decreased beta-cell apoptosis, while (P3
)PP also augmented beta-cell proliferation
in Ins1Cre/+;Rosa26-eYFP mice. Alpha-cell turnover rates were returned towards healthy
control levels by (P3
)PP intervention in both mouse models. In terms of islet cell lineage,
increased transition of alpha- to beta-cells as well as decreased beta- to alpha-cell differentiation were shown to contribute towards the enhancement of beta-cell area in (P3
)PP-treated
mice. Together these data reveal, for the first time, sustained NPY4R activation positively
modulates beta-cell turnover, as well as islet cell plasticity, to help preserve pancreatic islet
architecture following STZ-induced metabolic stress.