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 weight-lowering 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 Ins1<i>^Cre/+</i>;Rosa26-eYFP and Glu<i>^CreERT2</i>;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 Ins1<i>^Cre/+;</i>Rosa26-eYFP mice. Notably, pancreatic insulin content was augmented by (P³)PP treatment in both Ins1<i>^Cre/+;</i>Rosa26-eYFP and Glu<i>^CreERT2</i>;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 Ins1<i>^Cre/+;</i>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.