Introduction and Objective: Individuals with type 2 diabetes (T2D) have a higher proportion of senescent β-cells, which are dysfunctional. Senotherapeutics that improve β-cell function would be optimized by cell specificity which can be achieved by GLP-1 coupling. However, a deeper investigation of the bidirectional interplay between GLP-1 signaling and β-cell senescence is required. Methods: To evaluate the impact of senescence on incretin signaling, we performed pseudotime analysis of single-cell RNA sequencing (scRNA seq) data from human islets to map cellular trajectories that reflect the progression toward a senescent state. To determine whether senescence-associated changes in incretin signaling mirrored the changes seen in T2D, we then analyzed scRNA seq data pooled from three studies comparing islets from individuals with and without T2D. Furthermore, to investigate the impact of incretin signaling on senescence, we analyzed senescent marker expression using scRNA seq data from human islets treated with the GLP-1 agonist liraglutide. We then treated a human β-cell line with GLP-1 agonists and assessed expression of a panel of senescence and β-cell identity genes using qPCR. Results: The pseudotime analysis revealed an inverse expression pattern: incretin signaling genes elevated in non-senescent cell states were suppressed in senescent states, while those reduced in non-senescent states were induced in senescent states. Surprisingly, the expression of incretin receptors was increased in senescent states. When comparing individuals with and without T2D, increased incretin receptor expression was restricted to senescent β-cells, while the predominant non-senescent β-cell population showed reduced expression. Additionally, GLP-1 agonist treatment paradoxically promoted both senescence and β-cell identity genes. Conclusion: These results suggest a complex relationship between senescence and GLP-1 signaling in β-cells that warrants further investigation. Disclosure M. Jackson: None. K. Iwasaki: None. J. Hollister-Lock: None. S. Le: None. C. Cahill: None. C. Aguayo-Mazzucato: Consultant; Ended; Novo Nordisk, Sanofi.
Jackson et al. (Fri,) studied this question.