Pancreatic Ppy-expressing gamma-cells display mixed phenotypic traits and adaptive plasticity to engage insulin production

The cellular identity of pancreatic polypeptide (Ppy)-expressing γ-cells, the rarest pancreatic islet cell-type, remains elusive. Within islets, glucagon and somatostatin, released respectively from α- and δ-cells, modulate the secretion of insulin by β-cells. Dysregulation of insulin production raises blood glucose levels, leading to diabetes onset. Here, we present the genetic signature of human and mouse γ-cells. Using newly developed tools, we identified a set of genes and pathways defining their functional identity. We found that the γ-cell population is heterogeneous, with subsets of cells producing another hormone in addition to Ppy. These bihormonal cells share identity markers typical of the other islet cell-types. In mice, Ppy gene inactivation or conditional γ-cell ablation did not alter glycemia nor body weight. Interestingly, upon β-cell injury induction, γ-cells exhibited gene expression changes and some of them engaged insulin production, like α- and δ-cells. In conclusion, we provide a comprehensive characterization of γ-cells and highlight their plasticity and therapeutic potential. Transcriptomic profile of pancreatic Ppy-expressing cells using single cell and bulk RNA-seq Profile the transcriptomic landscape of Ppy-expressing cells and compare it to the other pancreatic endocrine cell types. RNA-seq of sorted alpha, beta, delta and gamma-cells from multiple transgenic mouse models. **Please note that the alpha and beta-cell data was downloaded from the accession number is GSE155519. All sequencing data were uploaded to, and aligned on the Galaxy project against Ensembl reference genome GRCm38.p6 (release 100) using STAR version 2.7.2b in 2-pass mapping mode. Aligned data were counted using HTSeq version 0.9.1 in union mode.