Background: Pancreatic polypeptide (PP) signalling plays an important role in energy homeostasis. Upon food ingestion, PP is released from pancreatic islet PP cells to induce satiety via the activation of its specific Y4 receptors (Y4R). Despite the close proximity of PP cells to other cell types within the islets that are critical in glucose regulation, the impact of the PP-Y4R signalling on beta cell function and glucose homeostasis, especially under obese conditions, has been much less studied.
Objectives: To investigate the role of the Y4 receptor signalling in regulating beta cell function and glucose homeostasis.
Methods: In this study, male Y4R deletion mice (Y4-/-) were fed a high-fat diet (HFD) for 10 weeks and glucose and insulin tolerance tests (GTT & ITT) were carried out. Islets were isolated from Y4-/- mice and controls (Y4+/+) for ex vivo glucose-stimulated insulin secretion (GSIS) assays and qPCR analysis to evaluate beta-cell function.
Results: Here, we reported that Y4-/- mice displayed improved glucose tolerance which was associated with increased insulin secretion, and this enhanced in vivo insulin secretory response during a GTT was confirmed during an ex vivo GSIS assay. Mechanistically, this improved beta-cell function in Y4-/- islets was associated with the upregulation of markers important for ER stress responses and lipid metabolism and beta-oxidation. Moreover, we also observed that Y4-/- islets displayed resilience under mechanical stress, and transplantation of Y4-/- islets into chemically induced type 1 diabetic mice accelerated the normalization of hyperglycaemia.
Conclusions: These findings highlight the significance of the PP-Y4R signaling in not only regulating feeding behaviour, but also modulating insulin secretion and glucose homeostasis. Manipulating Y4 receptor signalling in beta cells represents a promising therapeutic avenue for addressing insulin deficiency observed in type 1 diabetes pathology and during islet transplantation.