Int J Mol Sci. 2025 Apr 29;26(9):4215. doi: 10.3390/ijms26094215.
ABSTRACT
(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 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.
PMID:40362452 | PMC:PMC12071604 | DOI:10.3390/ijms26094215