Modulation of pancreatic beta-cell neuropeptide Y receptors as a novel therapeutic option for type 2 diabetes

Abstract

Following the considerable success of glucagon-like peptide-1 (GLP-1) receptor agonists in managing diabetes mellitus type 2 (T2DM) and obesity, endogenous peptides have garnered significant attention as potential therapeutic agents. Among these, the neuropeptide Y (NPY) family and its receptors are of particular interest due to their roles in regulating appetite as well as pancreatic islet cell dynamics. Pancreatic polypeptide (PP), a natural selective ligand to NPY4 receptors (NPY4R), initially gained recognition for its anorexigenic properties. Despite this, PP's clinical application was hindered by rapid dipeptidyl peptidase-4 (DPP-4) enzymatic degradation in the bloodstream, and further key challenges in developing stable and bioactive PP forms. However, recent advancements in peptide chemistry have renewed understanding of PP's function, particularly its role in beta-cell preservation, reignited interest in therapeutic application for diabetes and obesity. Within this thesis five novel PP analogues, fully resistant to DPP-4 action with significant anorectic and beta-cell preservation effects, have been characterised, including (P3)PP as a lead peptide. As such, (P3)PP was a particularly potent agent in vitro, with related prolonged bioactivity in vivo linked to very promising anorectic actions. Accordingly, chronic administration of (P3)PP in HFF-STZ induced diabetic mice demonstrated key metabolic benefits including reduced food intake, body weight and blood glucose levels as well as improving pancreatic beta-cell turnover. Moreover, (P3)PP exerted a direct impact on beta-cell proliferation and apoptosis, with the utilisation of transgenic Ins1cre/+;Rosa26-eYFP and GluCre;Rosa26-eYFP mice providing observations of (P3)PP’s ability to preserve beta-cell identity, facilitating beta- and alpha-cell transdifferentiation towards insulin-secreting phenotypes. To fully exploit the therapeutic potential of NPY4R activation, a combinational approach with low-dose Ex-4 have was employed, offering a treatment strategy with significant glucose-lowering and beta-cell preserving advantages, culminating in improved glucose tolerance. Additionally, five stable unimolecular peptides hybridising PP and GLP-1 are also presented iii within this thesis, each demonstrating anti-diabetic properties including preservation of beta-cells, reduction of food intake and improvement of glucose tolerance in overnight fasted mice. Taken together, this series of studies represent a novel approach to anti-diabetic therapy through modulation of NPY4R activity, revisiting and renovating PP-based therapy for the alleviation of obesity and related T2DM.

Thesis embargoed until 30 June 2026

Date of Award	Jun 2024
Original language	English
Supervisor	Nigel Irwin (Supervisor), Victor Gault (Supervisor) & Peter Flatt (Supervisor)